Search

PN‐943 is an orally stable, gastrointestinal‐restricted peptide that binds specifically to α4ß7 integrin on leukocytes, blocking leukocyte trafficking to and activation in the gut, inhibiting colon inflammation and reducing signs and symptoms of active ulcerative colitis. Two pharmacokinetic/pharmacodynamic studies were conducted in healthy volunteers. Study 1 was a first‐in‐human study with 40 male subjects receiving PN‐943, 100 to 1400 mg or placebo, as single doses and 57 male subjects receiving PN‐943, 100 to 1000 mg or placebo, as multiple doses. Study 2 was a randomized, crossover study comparing multiple doses of 450‐mg PN‐943 twice daily as a liquid solution and as an immediate‐release tablet in 10 subjects. No subjects discontinued due to treatment‐emergent adverse events. Consistent with the gastrointestinal‐restricted nature of the peptide, systemic exposure was minimal; there was an approximate dose‐proportional increase in area under the plasma concentration–time curve. There was minimal accumulation with once‐daily dosing and an absence of time‐dependent changes in pharmacokinetics. Administration of PN‐943 after a high‐fat meal reduced peak plasma concentration and area under the plasma concentration–time curve. There was minimal (

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels 45%, thereby potentially increasing their risk of thrombosis. Symptomatic iron deficiency represents a challenge in PV as it is commonly present at diagnosis [Ginzburg Leukemia 2018] and worsens after repeated and/or frequent TP, and often symptomatic from their iron deficiency. We hypothesized that both iron deficiency and expanded erythropoiesis in PV lead to suppression of hepcidin, the body's main negative regulator of iron metabolism, and that hepcidin suppression enhances iron absorption and availability for enhanced erythropoiesis in TP-requiring PV patients. We previously demonstrated that PTG-300, a hepcidin-mimetic, caused dose-related anemia in preclinical studies. In a phase 2 trial in β-thalassemia, PTG-300 leads to a sustained (3-7 days) decrease in serum iron and transferrin saturation (TSAT) but did not demonstrate off-target effects. The current study aims to compare the iron status and phlebotomy requirements in high TP-requiring PV patients before and during treatment with PTG-300 (Figure 1). Methods. PTG-300-04 is a 3-part Phase 2 trial consisting of (1) a 28-week dose-finding; (2) a 12-week blinded randomized withdrawal (1:1) PTG-300 vs placebo; and (3) a 52-week open label extension (Figure 1). Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and ≥3 phlebotomies with or without concurrent cytoreductive therapy to maintain hematocrit ≤45% in the 24 weeks prior to enrollment. PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly were adjusted to maintain hematocrit Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. After instruction, each of the patients self-administered the drug at home. Eight subjects have been treated for ≥3 months with PTG-300 (Figure 2a). Three subjects have been randomized. During the open label dose finding portion of the study, all subjects were phlebotomy-free with the exception of one subject. Three subjects completed part 1 (28 weeks) with no TP as compared to 3-5 TP required in a similar period prior to study initiation. During the 28-week dose-finding period, the hematocrit was continuously controlled below 45% in all but two subjects' (Figure 2b). Two subjects had hematocrits transiently >45% but remained below 45% after phlebotomy in one and dose increase in both. Furthermore, erythrocyte numbers decreased (Figure 2c) and MCV increased in all but two subjects. These findings suggest a redistribution of iron within erythropoiesis. Lastly, prior to treatment, mean iron-related parameters were consistent with systemic iron deficiency while serum ferritin increased progressively toward normal range. Most frequent adverse events were injection site reaction (ISR) reported by three patients. Most of the reactions were grade 1-2 and were transient in nature and no patient discontinued the drug. Conclusions. The current results indicate that PTG-300 is an effective agent for the treatment of PV, reversing iron deficiency and eliminating the need for TP in PV patients. Elimination of TP requirements for 7 months in TP-dependent PV patients is significant and unexpected. The effect of PTG-300 on PV-related symptoms is also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. PTG-300 looks very promising in eliminating the therapeutic phlebotomies in both low and high-risk patients. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Constellation Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding. Kuykendall:Blueprint Medicines: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Dynavax: Current equity holder in publicly-traded company. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Jannsen: Research Funding; Protagonist: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Verstovsek:PharmaEssentia: Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding. Hoffman:Forbius: Consultancy; Dompe: Research Funding; Protagonist: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Objectives IPX203 is an investigational oral extended-release capsule formulation of carbidopa and levodopa. The pharmacodynamics and efficacy of IPX203 were compared with immediate-release carbidopa-levodopa (IR CD-LD) in this open-label, rater-blinded, multicenter, crossover study in patients with advanced Parkinson disease (PD). Methods Twenty-eight patients were randomized to 2 weeks of treatment with IR CD-LD followed by IPX203 or IPX203 followed by IR CD-LD. Pharmacokinetic and motor assessments were conducted on days 1 and 15 of each treatment period. Efficacy was assessed using a 3-day PD diary. Pharmacodynamics were assessed by rater-blinded Movement Disorder Society—Unified Parkinson's Disease Rating Scale Part III and Investigator Assessment of Subject's Motor State. Results After a single dose, levodopa concentrations were sustained above 50% of peak concentration for 4.6 hours with IPX203 versus 1.5 hours with IR CD-LD (P < 0.0001). Based on the PD diary, patients experienced significantly less Off time with IPX203 as a percentage of waking hours than IR CD-LD (mean 19.3% vs 33.5%, respectively; P < 0.0001), translating into 2.3 hours less Off time than IR CD-LD with most of this improvement (1.9 hours) being Good On time. There was no significant difference in the amount of On time with troublesome dyskinesia between treatments. Pharmacodynamic assessments demonstrated similar outcomes in favor of IPX203 on day 1 and a significant predose benefit on motor examination after multiple dosing. Conclusions IPX203 demonstrated a sustained effect to reduce Off time and improve Good On time in patients with PD and motor fluctuations. Both treatments were well tolerated.

Background. IPX066 is an extended-release (ER) oral formulation of carbidopa-levodopa (CD-LD). Following an initial peak at about one hour, plasma LD concentrations are maintained for about 4-5 hours. Objective. To present dosing factors that may affect the successful conversion to ER CD-LD from other LD formulations. Methods. Two-phase 3 studies of ER CD-LD vs. immediate-release (IR) CD-LD (ADVANCE-PD) and vs. CD-LD + entacapone (CLE; ASCEND-PD) in subjects with advanced PD included a 6-week, open-label conversion to ER CD-LD prior to treatment randomization. The “converted” daily LD dose ratio and dose frequency for ER CD-LD were compared to the prior LD treatment regimens at study entry. Results. The average daily LD dose ratio at the end of dose conversion to ER CD-LD was approximately 2.1 for IR CD-LD and 2.8 for CLE. The final dose ratios tended to be slightly higher for participants taking lower LD doses at study entry but independent of dose frequency. ER CD-LD dose frequency increased with increasing LD dose and dose frequency at study entry. Participants on higher baseline LD doses ≥800 mg and dose frequencies ≥6 tended to have higher rates of discontinuation during conversion to ER CD-LD. Conclusions. Converting participants from other LD formulations to ER CD-LD is based on their current LD regimen. For the most common daily doses (≤1250 mg) and dose frequencies (NCT00974974, NCT01130493.

Objectives Extended-release (ER) carbidopa-levodopa (CD-LD) (IPX066/RYTARY/NUMIENT) produces improvements in "off" time, "on" time without troublesome dyskinesia, and Unified Parkinson Disease Rating Scale scores compared with immediate-release (IR) CD-LD or IR CD-LD plus entacapone (CLE). Post hoc analyses of 2 ER CD-LD phase 3 trials evaluated whether the efficacy and safety of ER CD-LD relative to the respective active comparators were altered by concomitant medications (dopaminergic agonists, monoamine oxidase B [MAO-B] inhibitors, or amantadine). Methods ADVANCE-PD (n = 393) assessed safety and efficacy of ER CD-LD versus IR CD-LD. ASCEND-PD (n = 91) evaluated ER CD-LD versus CLE. In both studies, IR- and CLE-experienced patients underwent a 6-week, open-label dose-conversion period to ER CD-LD prior to randomization. For analysis, the randomized population was divided into 3 subgroups: dopaminergic agonists, rasagiline or selegiline, and amantadine. For each subgroup, changes from baseline in PD diary measures ("off" time and "on" time with and without troublesome dyskinesia), Unified Parkinson Disease Rating Scale Parts II + III scores, and adverse events were analyzed, comparing ER CD-LD with the active comparator. Results and conclusions Concomitant dopaminergic agonist or MAO-B inhibitor use did not diminish the efficacy (improvement in "off" time and "on" time without troublesome dyskinesia) of ER CD-LD compared with IR CD-LD or CLE, whereas the improvement with concomitant amantadine failed to reach significance. Safety and tolerability were similar among the subgroups, and ER CD-LD did not increase troublesome dyskinesia. For patients on oral LD regimens and taking a dopaminergic agonist, and/or a MAO-B inhibitor, changing from an IR to an ER CD-LD formulation provides approximately an additional hour of "good" on time.

Background & Aims Oral therapies targeting the integrin α4β7 may offer unique advantages for the treatment of inflammatory bowel disease. We characterized the oral α4β7 antagonist peptide PTG-100 in preclinical models and established safety, pharmacokinetic/pharmacodynamic relationships, and efficacy in a phase 2a trial in patients with ulcerative colitis (UC). Methods In vitro studies measured binding properties of PTG-100. Mouse studies measured biomarkers and drug concentrations in blood and tissues. The phase 1 study involved healthy volunteers. In phase 2a, patients with moderate to severe active UC were randomized to receive PTG-100 (150, 300, or 900 mg) or placebo once daily for 12-weeks. Results PTG-100 potently and selectively blocks α4β7. Oral dosing of PTG-100 in mice showed high levels of target engagement and exposure in gut-associated lymphoid tissues. In healthy volunteers, PTG-100 showed dose-dependent increases in plasma exposure and blood target engagement. Although this phase 2a study initially did not meet the primary endpoint, a blinded reread of the endoscopy videos by a third party indicated clinical efficacy in conjunction with histologic remission at doses correlating with less than 100% receptor occupancy in peripheral blood. Conclusions PTG-100 showed local gastrointestinal tissue target engagement and inhibition of memory T-cell trafficking in mice. It was safe and well tolerated in phase 1 and 2 studies. Phase 2a data are consistent with biological and clinical response and showed a dose response reflecting similar activities in preclinical models and healthy individuals. These data suggest that local gut activity of an oral α4β7 integrin antagonist, distinct from full target engagement in blood, are important for efficacy and the treatment of UC. (ClinicalTrials.gov, Number NCT02895100; EudraCT, Number 2016-003452-75)

Background. Polycythemia vera (PV) patients are treated with periodic therapeutic phlebotomy (TP) alone or in combination with either hydroxyurea (HU), ruxolitinib (RUX) or interferon (IFN) to maintain hematocrit (HCT) levels below 45% as per NCCN guidelines. Since patients are seen periodically, PV patients may spend significant time with HCT levels above 45%, thereby increasing their risk of thrombosis [Marchioli NEJM 2013]. PV is associated with systemic symptoms with fatigue. These fatigue-related symptoms are found to be the most prevalent and severe as reported in an international survey among PV patients [Scherber Cancer 2016]. Symptomatic iron deficiency represents an unaddressed clinical challenge to PV patients as most PV patients have iron deficiency at diagnosis due to increased iron utilization [Ginzburg Leukemia 2018]. The iron deficiency worsens after repeated TP. We have demonstrated in a phase 2 study that rusfertide (PTG-300) has a good tolerability profile and achieves HCT control in PV patients with improvement in iron deficiency. Methods. This is a Phase 3, multicenter, global, randomized trial that compares the efficacy and safety of rusfertide compared to placebo when added on to current therapy for PV (Figure 1). The study population is PV subjects who require frequent phlebotomies to control their hematocrit with or without concurrent therapy. This is a three-part study in subjects with polycythemia vera: - Part 1a: randomized, double-blind, placebo-controlled, add-on parallel-group period for 32 weeks. Subjects will be stratified by their ongoing PV treatment and randomized 1:1 to rusfertide or placebo added-on to their ongoing PV treatment. - Part 1b: open-label treatment phase during which all subjects who complete Part 1a successfully will receive rusfertide for 20 weeks (Week 32 through Week 52). - Part 2: Long term extension (LTE) phase during which all subjects who complete Part 1b will continue to receive rusfertide for 32 weeks (Week 52 to Week 84). Inclusion Criteria: Approximately 250 subjects will be randomized. Eligibility criteria include PV diagnosis (by 2016 WHO criteria) and frequent phlebotomies with or without concurrent cytoreductive therapy to maintain HCT below 45% in the 6 months prior to enrollment in Part 1. Eligible subjects will continue to receive their therapy at screening for PV (phlebotomy alone (TP) or cytoreductive therapy + TP) and must have a hematocrit The "add on" design allows subjects to receive standard cytoreductive therapy to control WBC and/or platelets and to receive rusfertide/placebo. The dose of cytoreductive therapy in Part 1a and Part 1b may be decreased for safety but may not be increased for efficacy including control of hematocrit, elevated platelets and/or WBC. Primary endpoint: Proportion of subjects achieving a response starting at Week 20 through Week 32 (inclusive) who receive rusfertide compared to placebo. A response is defined as absence of phlebotomy eligibility defined as either: 1. a confirmed hematocrit ≥45% and that is at least 3% higher than the baseline hematocrit (value immediately prior to randomization at Week 0); confirmation required within 1 to 7 days, or 2. a hematocrit ≥48%. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; PharmaEssentia: Research Funding; Protagonist Therapeutics: Research Funding; CTI BioPharma: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Kuykendall: Pharmaessentia: Honoraria; Protagonist: Consultancy, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria; Abbvie: Honoraria; Incyte: Consultancy; Blueprint: Honoraria. Hoffman: AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding; Novartis: Other: Data Safety Monitoring Board, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Kartos Therapeutics, Inc.: Research Funding. Pemmaraju: Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; LFB Biotechnologies: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; Sager Strong Foundation: Other; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; CareDx, Inc.: Consultancy; Springer Science + Business Media: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. O'Connor: Protagonist Therapeutics: Current Employment. Gupta: Protagonist Therapeutics: Current Employment. Kiladjian: Taiho Oncology, Inc.: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

Introduction: Patients with hereditary hemochromatosis (HH) require continued phlebotomies to limit end-organ damage. Approximately 25% of patients in maintenance felt receiving phlebotomies was "inconvenient" or "very inconvenient" (Brisott et al, 2011). Patient compliance with phlebotomies generally declines with time (Hicken et al, 2003), and therapeutic phlebotomies may not be medically suitable for some HH patients. Rusfertide, a peptide mimetic of hepcidin, is an effective regulator of iron distribution and utilization that has demonstrated control of iron in an animal model of HH. Methods: We conducted an open-label, dose-finding efficacy study that investigated subcutaneous rusfertide in HH patients on a stable phlebotomy regimen of 0.25 to 1 phlebotomy per month for at least 6 months. Patients with clinical laboratory abnormalities and those receiving iron chelation therapy or erythrocytapheresis were excluded. Subjects received individually titrated rusfertide doses once or twice a week to maintain transferrin saturation (TSAT) below 45% and were followed for 6 months. Study measures included TSAT, serum iron, transferrin and ferritin, liver iron concentration (LIC) measured by MRI, and adverse events (AEs). Results: Sixteen subjects (10 male/6 female) were enrolled. Mean age and weight were 62.5 years and 88.1 kg, respectively. LIC values were maintained at pre-study levels, with minimal use of phlebotomies during the duration of the study (Figure 1A). Average pre-study phlebotomy rate was 0.27 phlebotomies/month compared to 0.03 phlebotomies/month during the study (p Conclusions: Rusfertide demonstrated a pharmacodynamic effect in reducing TSAT and serum iron, with corresponding significant reduction in the number of phlebotomies, and with LIC maintained at pre-study levels with minimal use of phlebotomies. These data indicate rusfertide was well tolerated in patients with HH and controls LIC, supporting development of rusfertide as a potential treatment for HH. Figure 1 Figure 1. Disclosures Kowdley: PTG: Consultancy, Research Funding. Modi: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gupta: Protagonist Therapeutics: Current Employment.

Background. Polycythemia (PV) patients with hematocrit above 45% are at increased risk of thrombotic complications and are treated with phlebotomy and/or cytoreductive therapy to reach a hematocrit target below 45%. Rusfertide (PTG-300) is a peptidic mimetic of hepcidin that is being developed for treatment of polycythemia vera (PV). A Phase 2 trial has indicated that rusfertide is effective at reducing the number of phlebotomies and maintaining hematocrit below 45% without phlebotomy in PV patients who are either high-risk or low-risk, patients treated with cytoreductive therapy (hydroxyurea, interferon, ruxolitinib) and patients treated with phlebotomy alone (Kremyanskaya, ASH 2020). The current trial (PTG-300-08) tested the ability of rusfertide to normalize hematocrit in PV patients with elevated hematocrit without instituting phlebotomy treatment to normalize hematocrit to below 45% in PV patients without requiring phlebotomy and/or cytoreductive treatment. Methods. Eligible study subjects were diagnosed with PV (in accordance with the WHO 2016 criteria), had baseline hematocrit above 48%, and a history of 3 or more hematocrit values above 48% in the year prior to enrollment. High-risk and low-risk subjects treated with phlebotomy alone or with concurrent cytoreductive therapy were eligible. Rusfertide was added on to each subject's current therapy. The initial rusfertide dose was 40 mg administered subcutaneously twice weekly. When each subject's hematocrit was below 45%, the dosing schedule was changed to weekly and the rusfertide dose was adjusted to maintain hematocrit below 45%. Results. Sixteen subjects (12 male and 4 females) have been enrolled. The mean age is 56.1 years; the mean time since diagnosis is 3.74 years; 10 subjects are low risk PV; 12 subjects are receiving concurrent hydroxyurea and 4 subjects were not receiving cytoreductive therapy. Baseline values (mean, min-max) HCT (51.0%, 47.4 - 59), WBC (12,338/µL, 7,000 - 24,600), RBCs (5.9x10 6/µL, 4.3 - 7.6), platelets (486,500/µL, 242,000 - 904,000). All subjects had rapid decreases in hematocrit to below 45% without the use of phlebotomy (Figure 1a). Hematocrit levels remained well controlled after falling below 45% as investigators reduced rusfertide dose to maintenance once weekly regimen. Hemoglobin (Figure 1b) fell rapidly. Erythrocyte counts (Figure 1c) also fell rapidly, indicating that decreased hematocrit is due to decreased erythrocytosis. For the 11 subjects with adequate follow-up, the mean rate of absolute hematocrit decrease was 1.76% per week (median: 1.81%/week; min - max: 0.65 - 2.69%) and the mean time to reach goal hematocrit below 45% was 4.79 weeks (median: 4.14 weeks, min - max: 3.57 - 8.14). Eight subjects reported adverse events (AEs). Injection site reactions (ISRs) occurred in 7 subjects and were mild or moderate in severity. The most common ISRs were erythema (n=7), induration (n=5) and pruritis (n=2). Adverse events other than ISRs that occurred in 2 or more subjects were hypertension (n=2), pyrexia (n=2) and thrombocytosis (n=2). There were two serious adverse events (worsening migraine and pleuritic chest pain) and both were considered unrelated to rusfertide. Overall, rusfertide was well tolerated. Conclusions. This study demonstrates that induction therapy with twice weekly rusfertide administration was effective in rapidly achieving target hematocrit below 45% without phlebotomy in all PV patients which was then successfully maintained with weekly rusfertide treatment. Moreover, the twice weekly injections of rusfertide used to rapidly lower hematocrit levels were safe and well tolerated. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Gupta: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Hoffman: Kartos Therapeutics, Inc.: Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Novartis: Other: Data Safety Monitoring Board, Research Funding; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding.

Parkinson’s disease (PD) is a chronic progressive neurological disorder characterized by resting tremor, rigidity, bradykinesia, gait disturbance, and postural instability. Levodopa, the precursor to dopamine, coadministered with carbidopa or benserazide, aromatic amino acid decarboxylase inhibitors, is the most effective and widely used therapeutic agent in the treatment of PD. With continued levodopa treatment, a majority of patients develop motor complications such as dyskinesia and motor ‘on-off’ fluctuations, which are, in part, related to the fluctuations in plasma concentrations of levodopa. A new extended-release (ER) carbidopa–levodopa capsule product (also referred to as IPX066) was developed and approved in the US as Rytary® and in the EU as Numient®. The capsule formulation is designed to provide an initial rapid absorption of levodopa comparable to immediate-release (IR) carbidopa–levodopa, and to subsequently provide stable levodopa concentrations with reduced peak-to-trough excursions in plasma concentrations in order to reduce motor fluctuations associated with pulsatile stimulation of dopamine receptors and to minimize dyskinesia. Phase III studies of this ER carbidopa–levodopa capsule formulation in patients with PD have shown a significant reduction in ‘off’ time compared with IR carbidopa–levodopa and carbidopa–levodopa–entacapone. We present a review of the clinical pharmacokinetics and pharmacodynamics of this ER product of carbidopa–levodopa in healthy subjects and in patients with PD.

Background IPX066 (Rytary®; carbidopa and levodopa [CD-LD] extended-release capsules) was designed to achieve therapeutic LD plasma concentrations within 1 h of dosing and maintain LD concentrations for a prolonged duration in early or advanced Parkinson's disease (PD). Methods In this open-label study, patients underwent 6 weeks of conversion to IPX066 from their prior controlled-release (CR) ± immediate-release (IR) CD-LD therapy and 6 months of maintenance (with an additional 6 months of IPX066 at some sites). Clinical utility was assessed at both the end of conversion and maintenance. Results Among 43 patients initiated on IPX066, 33 completed conversion. The mean LD conversion ratio was 1.8 among 30 patients previously on CR plus IR (and 1.5 among 3 previously taking CR alone). The mean IPX066 dosing frequency was 3.5 times/day compared with 2.6 times/day for CR plus 4.6 times/day for IR previously (and 4.7 times/day for CR alone). By patient and clinician global improvement ratings after 6-month maintenance, ≥ 43.8% of patients were much or very much improved from their previous treatment, and ≥ 68.8% were at least minimally improved. Adverse events were consistent with those reported in prior IPX066 studies. Conclusions These results suggest that advanced PD patients using CR CD-LD ± IR can be safely converted to IPX066, with high likelihood of achieving a stable regimen, less frequent LD dosing, and improved overall clinical benefit. Trial registration: Clinicaltrials.gov NCT01411137 .

Background. The majority of PV patients are iron deficient at diagnosis [Ginzburg Leukemia 2018]. PV patients are treated with periodic therapeutic phlebotomy (TP) in order to maintain hematocrit levels 70% within 12 hours and the effect persists for 3-7 days. In a phase 2 trial in β-thalassemia, PTG-300 also decreased serum iron and TSAT but did not demonstrate off-target effects. The current study aims to compare the iron status in frequent TP-requiring PV patients before, during, and after treatment with PTG-300. Methods. Polycythemia patients who met 2016 WHO criteria for diagnosis were enrolled in the 28-week dose finding part of a Phase 2 trial. All patients required ≥3 phlebotomies with or without concurrent cytoreductive therapy over 6 months prior to enrollment. Patients were given PTG-300 doses of 10, 20, 40, 60 and 80 mg administered subcutaneously weekly in individualized adjustment to maintain hematocrit Results. Thirteen subjects were enrolled to date: 7/13 with low risk, mean age 57.4 years (range 31-74). Six receiving TP alone, 6 on concurrent hydroxyurea, 1 on concurrent interferon; TP in the 24 weeks prior to enrollment = 3-9; median time between TP = 42 days. All subjects-maintained hematocrit Conclusions. The current results indicate that PTG-300 is an effective agent for the controlling hematocrit and reversing iron deficiency. The effect of PTG-300 on PV-related symptoms and those of iron deficiency, are also being evaluated. Continued patient enrollment will enable more definitive conclusions regarding the efficacy and safety of hepcidin mimetic PTG-300 in PV patients with high TP requirements. Disclosures Kremyanskaya: Incyte Corporation: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding. Kuykendall:Novartis: Research Funding; Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding. Yacoub:Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support. Yang:AROG: Research Funding; AstraZeneca: Research Funding; Protagonist: Research Funding; Jannsen: Research Funding. Gupta:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Khanna:Protagonist: Current Employment, Current equity holder in publicly-traded company. Hoffman:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Forbius: Consultancy; Protagonist: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; Protagonist Therapeutics: Research Funding; NS Pharma: Research Funding; CTI Biopharma Corp: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; PharmaEssentia: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding.

BACKGROUND Polycythemia Vera (PV) is a rare myeloproliferative neoplasm associated with an increased production of red blood cells, white blood cells, and platelets. Most frequent treatment includes phlebotomy, hydroxyurea, interferon, and ruxolitinib. Current NCCN guideline recommends managing HCT levels to below 45%. The objective of this study was to determine real-world standards of care and patient characteristics, and to observe how treatment decisions vary by HCT level and thrombosis risk. METHODOLOGY We conducted a retrospective study using Symphony Health's longitudinal transactional healthcare claims database that includes prescription, medical and hospital claims across > 4,900 US payers representing 86% of US lives. Eligible patients had at least one ICD-10 diagnosis code for PV and at least one of the treatments including phlebotomy, hydroxyurea, busulfan, interferon, and ruxolitinib between Jan 1, 2018 and Dec 31, 2019 (index period). For eligible patients, all prior treatment history initiated as far back as January 2010 was used to report therapy changes. Patients were also required to have at least one PV diagnosis within a year of treatment initiation and at least 2 HCT lab results during the index period. PV treatment changes and characteristics were studied. RESULTS Out of 28,306 patients with PV, 4,264 patients had HCT lab data for 2 years (index period). Median duration of follow-up was 854 days (range 98-3,373days). Patient therapy duration was from 1 to 9 years. Median patient age was 65 (range 11-94), with 1,451 (34%) patients aged less than 60, 2,813 (66%) 60 years or older, and a substantial male predominance (62% vs 38%). 1,247 (29%) patients were classified as Low Risk (age< 60 with no TE history) and 3,017 (71%) patients as High Risk. Within the High-Risk group, 2,224 (52%) were age>60 without prior TE, 204 (5%) were age60 with prior TE. For Low Risk patients' initial treatment was phlebotomy alone (85%) and a total of 73% of all Low Risk patients remained on phlebotomy alone. For High Risk patients' initial treatment was phlebotomy alone (60%) and 43% all of High-Risk patients remained on phlebotomy alone (Figure 1). The median HCT prior to treatment initiation was 52.9% and 48% during treatment. 936 (22%) patients achieved NCCN treatment guidelines with HCT levels always remaining under 45%, and 1,226 (29%) patients had HCT levels controlled between 45% and 50%. However, 2,102 (49%) patients had some or all HCT levels> 50% (Figure 2). With the most recent lab test, 2,180 (51%) of patients still had HCTs above 45% and 804 (19%) were still above 50%. In a sub-cohort of 653 High Risk patients with a prior TE and up to 5 years of follow up, 236 (36%) had at least one other TE; for the 1,774 High Risk patients who did not have the history of thrombosis, 161(9%) had at least one TE (Table 2). The most common TE since treatment began in patients with prior TE were deep vein thrombosis (n= 92 patients, 14%) and stroke (n= 95 patients, 15%). Among High Risk patients (n=397) who had another thrombotic event, 180 (45%) were treated by phlebotomy only and never switched to any other therapies. CONCLUSIONS Despite currently available treatments in US, patients' HCT level after treatment were higher than recommended as per guidelines. Failure to maintain HCT less than 45% increases the risk of future thrombotic events as shown by 36% of patients with prior TE experiencing another TE within the next 5 years. Disclosures Verstovsek: Sierra Oncology: Consultancy, Research Funding; ItalPharma: Research Funding; Blueprint Medicines Corp: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Genentech: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; CTI Biopharma Corp: Research Funding. Han:Protagonist Therapeutics: Consultancy. Chun Hayes:Protagonist: Consultancy. Woody:Protagonist: Current Employment. Valone:Protagonist: Current Employment. Gupta:Protagonist: Current Employment.

OBJECTIVE IPX203 is an investigational oral extended-release capsule formulation of carbidopa-levodopa (CD-LD). The aim of this study was to characterize the single-dose pharmacodynamics, pharmacokinetics, and safety of IPX203 in subjects with advanced Parkinson disease compared with immediate-release (IR) CD-LD and extended-release CD-LD (Rytary). METHODS This was a randomized, open-label, rater-blinded, multicenter, single-dose crossover study. Blinded clinicians assessed subject's motor state and Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III scores for up to 10 hours postdose. Duration of effect was determined using improvement thresholds in the MDS-UPDRS part III. RESULTS Levodopa concentrations increased rapidly and similarly across all 3 treatments and were sustained for a longer duration after IPX203 dosing. All treatments exhibited a rapid onset of pharmacodynamic effect, whereas IPX203 had a significantly longer duration of effect based on MDS-UPDRS part III scores compared with IR CD-LD (P < 0.0001) and Rytary (P ≤ 0.0290). IPX203 had a 2.7-hour advantage over IR CD-LD (P < 0.0001) and a 0.9-hour advantage over Rytary in "off" time (P = 0.023) and in "good on" time (2.6 hours more than IR CD-LD, P < 0.0001; 0.9 hours more than Rytary, P = 0.0259) as measured by the Investigator Assessment of Subject's Motor State. Subjects were 77% more likely to require rescue following IR CD-LD treatment compared with IPX203 (hazard ratio, 0.23; P < 0.0001). More subjects reported treatment-emergent adverse effects during IR CD-LD (28.0%) and IPX203 (19.2%) than during Rytary (8.0%) treatment. CONCLUSIONS Compared with Rytary and IR CD-LD, IPX203 had a longer pharmacodynamic effect consistent with LD pharmacokinetics for the 3 treatments. The safety and tolerability of IPX203 were similar to those of IR CD-LD and Rytary.

Levodopa (LD) combined with a peripheral inhibitor of aromatic L-amino acid decarboxylase, such as carbidopa (CD), continues to be the most effective treatment of Parkinson disease and is well tolerated at all stages of the disease.1–3 Immediate-release formulations of LD require frequent dosing because of the short half-life of LD and result in marked fluctuations in the LD plasma concentrations. The pulsatile LD profile results in fluctuations in the clinical response such as on-off and wearing off and may play an important role in LD-induced dyskinesia.4,5 Intravenous and intraduodenal infusion of LD provide more stable plasma concentrations and can result in a smoother clinical response in patients with motor fluctuations.6–8 However, intravenous infusion is not practical for long-term therapy, and duodenal infusion requires surgery and may only be appropriate for the most severe patients. An oral product that provides more consistent LD absorption and more stable plasma concentrations would address a major unmet clinical need to enhance efficacy and reduce or prevent motor oscillations and drug-induced dyskinesias.9 However, current sustained-release formulations of CD-LD and the addition of a cathechol-O-methyltransferase inhibitor (eg, entacapone) to immediate-release CD-LD have been of limited value.10,11 Controlled-release formulations have been associated with erratic absorption, variable plasma concentrations, and a delayed onset of effect.12,13 Carbidopa-LD products containing entacapone have been associated with a shorter time to onset of dyskinesia and increased frequency of dyskinesia compared with CD-LD products.14 IPX066 (RYTARY [CD and LD]; Impax Laboratories, Inc, Hayward, Calif) is an extended-release multiparticulate capsule formulation of CD-LD that has demonstrated efficacy in patients with early and advanced Parkinson disease.15,16 IPX066 capsules are available in a 1:4 ratio of CD:LD in 4 CD-LD dose strengths: 23.75–95, 36.25–145, 48.75–195, and 61.25–245 mg of CD-LD. Food has been reported to affect the absorption of various drugs and, in particular, affect the performance of LD formulations.17–19 Absorption of LD occurs mainly in the proximal third of the small intestine. Delayed gastrointestinal transit may affect CD-LD absorption. Gastric emptying is affected by the composition and physicochemical properties of a meal. In addition, LD and its derivative dopamine have also been reported to affect gastric emptying.20,21 The objectives for this investigation were to characterize the dose proportionality of the 4 dose strengths of IPX066 capsules and to compare the pharmacokinetics of 1 and 2 capsules of the highest strength (61.25-245 mg of CD-LD). In addition, the effect of a high-fat, high-calorie breakfast and the effect of sprinkling the capsule contents on applesauce on the pharmacokinetics of IPX066 were assessed.

Robert A Hauser,1 Aaron Ellenbogen,2 Sarita Khanna,3 Suneel Gupta,3 Nishit B Modi3 1Departments of Neurology, Molecular Pharmacology, and Physiology, University of South Florida, Tampa, FL, USA; 2Quest Research Institute, Bingham Farms, MI, USA; 3Impax Laboratories, Inc., Hayward, CA, USA Background: In patients with Parkinson’s disease (PD), oral dosing of extended-release carbidopa-levodopa (Rytary, IPX066 [ER CD-LD]) achieves peak levodopa plasma concentrations within 1 hour and maintains them for 4–6 hours. Aims: To compare the onset and duration of ER CD-LD benefit with those of immediate-release carbidopa-levodopa (IR CD-LD) in PD patients with motor fluctuations, using crossover data, and to evaluate which threshold values of improvement in finger-tapping and Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores yield results most similar to those for trained raters’ “on”/“off” assessments. Methods: Patients underwent serial “on”/“off” rating and provided serial finger-tapping and UPDRS motor scores after receiving, in an “off” state, their usual morning IR dose or an ER dose designed to produce a similar levodopa peak concentration. Predefined improvement thresholds for analysis were 10%, 15%, and 20% increases in finger-tapping score and 2.5, 5, 7, and 11-point decreases in UPDRS motor score. Serial plasma samples were assayed for levodopa. Results: Among 27 patients, mean time to onset of an “on” state was similar for ER compared with IR CD-LD (0.83 vs 0.81 hour), but mean duration was significantly longer for ER CD-LD than for IR CD-LD (5.56 vs 2.69 hours; P

Background Due to the short half-life of levodopa, immediate-release carbidopa-levodopa (IR CD-LD) produces fluctuating LD concentrations, contributing to a risk of eventual motor complications. IPX066 was designed to rapidly attain therapeutic LD concentrations and maintain them to allow a dosing interval of ∼6 hours. Objective To extensively analyze the dosing data collected in IPX066 studies during open-label conversions from IR CD-LD alone or with entacapone (CLE) and identify patterns relevant for managing conversion in the clinical setting. Methods Patients had ≥2.5 hours/day of "off" time despite a stable IR or CLE regimen. Suggested initial dosing conversion tables based on prior LD daily dosage were provided. Results Of 450 patients previously treated with IR CD-LD and 110 with CLE, 87.3% and 82.7% completed conversion to IPX066, respectively. At the end of conversion, average IPX066 LD daily dosages were higher than pre-conversion dosages, with a mean conversion ratio of 2.1±0.6 for IR CD-LD and 2.8±0.8 for CLE; >90% of patients took IPX066 3 or 4 times/day, compared with a median of 5 times/day at baseline in both studies. After conversion, daily "off" time significantly decreased, with no significant increase in troublesome dyskinesia. The most common adverse event reported during conversion was nausea, with an incidence of 5.3% for conversion from IR and 7.3% from CLE. Conclusions Among PD patients with substantial "off" time, a majority were safely converted to IPX066. The sustained LD profile from the IPX066 formulation allowed an increase in LD dose accompanied by improved motor functions, without increased troublesome dyskinesia.

IPX066 (extended-release carbidopa-levodopa [ER CD-LD]) is an oral extended-release capsule formulation of carbidopa and levodopa. The single-dose pharmacokinetics of ER CD-LD (as 2 capsules; total dose, 97.5 mg-390 mg CD-LD) versus immediate-release (IR) CD-LD (25 mg-100 mg), sustained-release (CR) CD-LD (25 mg-100 mg), and CD-LD-entacapone (25 mg-100 mg-200 mg) was evaluated in healthy subjects. Following IR dosing, LD reached peak concentrations (Cmax) at 1 hour; LD concentrations then decreased rapidly and were less than 10% of peak by 5 hours. With CR CD-LD and CD-LD-entacapone, LD Cmax occurred at 1.5 hours, and concentrations were less than 10% of peak by 6.3 and 7.5 hours, respectively. The initial increase in LD concentration was similar between ER CD-LD and IR CD-LD and faster than for CR CD-LD and CD-LD-entacapone. LD concentrations from ER CD­­-LD were sustained for approximately 5 hours and did not decrease to 10% of peak until 10.1 hours. Dose-normalized LD Cmax values for ER CD-LD were significantly lower (P< .05) than for the other CD-LD products. Bioavailability of LD from ER CD-LD was 83.5%, 78.3%, and 58.8% relative to IR CD-LD, CR CD-LD, and CD-LD-entacapone, respectively.

Background and Objective IPX066 is a multiparticulate extended-release formulation of carbidopa–levodopa, designed to produce prolonged therapeutic levodopa plasma concentrations. This 9-month open-label extension study assessed its long-term safety and clinical utility in early and advanced Parkinson’s disease (PD). Methods Participants were enrolled from two phase III IPX066 studies and one open-label phase II study. Early PD patients were titrated to an appropriate dosing regimen while advanced patients started with regimens established in the antecedent studies. Adjustment was allowed throughout the extension. Clinical utility measures included the Unified Parkinson’s Disease Rating Scale (UPDRS) and Patient Global Impression (PGI) ratings. Results Among 268 early PD patients, 53.4 % reported adverse events (AEs) and 1.1 % (three patients) discontinued due to AEs; the most frequent AEs were nausea (5.6 %) and insomnia (5.6 %). Among 349 advanced patients, 60.2 % reported AEs and 3.7 % (13 patients) discontinued due to AEs; the most frequent AEs were dyskinesia (6.9 %) and fall (6.6 %). At month 9 (or early termination), 78.3 % of early patients were taking IPX066 three times daily (median: 720 mg/day) and 87.7 % of advanced patients were taking IPX066 three or four times daily (median: 1450 mg/day). Adjusting for 70 % bioavailability relative to immediate-release (IR) carbidopa–levodopa, the median dosages correspond to ~500 and ~1015 mg/day of IR levodopa in early and advanced PD, respectively. Based on the plasma profiles previously observed in PD patients, the IPX066 regimens in the extension can be estimated to provide a levodopa Cmax (maximum plasma drug concentration) similar to or lower than that provided by IR regimens during the antecedent trials. UPDRS and PGI findings showed sustained treatment effects throughout the extension. Conclusion During 9 months of extended use, IPX066 exhibited a safety/tolerability profile consistent with dopaminergic PD therapy.

Introduction: Carbidopa-levodopa extended-release capsules (ER CD-LD, IPX066) significantly improve motor symptoms and activities of daily living in early and advanced Parkinson’s disease (PD). ER CD-LD produces an initial peak in plasma levodopa concentrations at about one hour, which are maintained for about 4–5 hours before declining.

Introduction: Carbidopa-levodopa extended-release capsules (ER CD-LD, IPX066) significantly improves motor symptoms and activities of daily living in early and advanced Parkinson’s disease (PD). ER CD-LD produces an initial peak in plasma levodopa concentrations at about one hour, which are maintained for about 4–5 hours before declining.

The objective of the study was to compare the pharmacokinetics, motor effects, and safety of IPX066, a novel extended-release formulation of carbidopa-levodopa, with an immediate-release carbidopa-levodopa formulation in advanced Parkinson's disease. We performed an open-label crossover study in 27 subjects with advanced Parkinson's disease experiencing motor fluctuations on levodopa therapy. Subjects were randomized 1:1 to 8 days' treatment with either immediate-release carbidopa-levodopa followed by IPX066 or IPX066 followed by immediate-release carbidopa-levodopa. Pharmacokinetic and motor assessments were undertaken on day 1 for 8 hours (following a single dose) and on day 8 for 12 hours (during multiple-dose administration). Following a single dose of IPX066 or immediate-release carbidopa-levodopa, plasma levodopa concentrations increased at a similarly rapid rate and were sustained above 50% of peak concentration for 4 hours with IPX066 versus 1.4 hours with immediate-release carbidopa-levodopa (P < .0001). Multiple-dose data showed IPX066 substantially reduced variability in plasma levodopa concentrations despite a lower dosing frequency (mean, 3.5 vs 5.4 administrations per day). In addition, total levodopa exposure during IPX066 treatment was approximately 87% higher, whereas the increase in levodopa C(max) was approximately 30% compared with immediate-release carbidopa-levodopa. Both products were well tolerated. IPX066 provided more sustained plasma levodopa concentrations than immediate-release carbidopa-levodopa. Larger, longer-term, well-controlled studies should be conducted to provide rigorous assessment of the clinical effects of IPX066.

To examine the pharmacokinetics (PKs) and pharmacodynamics (PDs) of OROS methylphenidate (OROS MPH) dosed once daily (QD) versus an early standard regimen (immediate-release [IR] MPH dosed three times daily [TID]) under various breakfast conditions.This single-center, double-blind, double-dummy, randomized, crossover study of OROS MPH (NCT00269815) in children aged 6 to 12 years with attention-deficit/hyperactivity disorder evaluated the PKs and PDs of MPH given with different breakfast conditions: OROS MPH administered after a high-fat breakfast, after a normal breakfast, or after fasting and IR MPH administered after a normal breakfast or after fasting in the morning and at two subsequent time points during the day. To maximize information, patients were divided into two groups, each receiving three of the five treatments for 1 day in a three-period, randomized, crossover design. Patients were assigned to 1 of 3 dosage levels (OROS MPH 18, 36, and 54 mg QD, and an assumed equivalent regimen of IR MPH 5, 10, and 15 mg given TID) based on their prestudy established clinical dose of IR MPH. PD measurements included Combined-Attention and Deportment scores on a rating scale of school behavior (the Swanson, Kotkin, Agler, M-Flynn, and Pelham), global assessments of efficacy, and activity monitor levels during academic seatwork. Serial blood samples for PK analysis were taken predose, and then every 60 to 90 minutes until 11.5 hours postdose. Vital signs were assessed predose, and then every 1.5 to 2.5 hours until 11.5 hours postdose.Of the 32 patients enrolled, 31 completed the study. The PK profiles for MPH after OROS MPH administration were similar under all conditions (with normal, high-fat breakfast, or fasting). No bioequivalence tests of OROS MPH and IR MPH under various breakfast conditions were done because there were so few patients in each dose level of treatment. The two IR MPH conditions (after normal breakfast and fasting) were not compared. The drug-to-metabolite ratios (area under the curve) for all OROS MPH and IR MPH treatments were similar. OROS MPH and IR MPH provided a similar therapeutic effect, irrespective of breakfast conditions, as demonstrated by the Swanson, Kotkin, Agler, M-Flynn, and Pelham Attention and Deportment measures and global assessments. No serious adverse events, no deaths, and no clinically significant changes in vital signs were reported, except for one patient who was discontinued early because of repeated systolic blood pressure elevations on study day 1.The results of this study demonstrate that in children with attention-deficit/hyperactivity disorder, administering OROS MPH with or without food produces similar PK and PD profiles.

Background: Modified-release (MR) products are complex dosage forms designed to release drug in a controlled manner to achieve the desired efficacy and safety profiles. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. Objective: This paper is a summary report of the American Association of Pharmaceutical Scientists, International Pharmaceutical Federation, and Product Quality Research Institute workshop titled "Challenges and Opportunities in Establishing Scientific and Regulatory Standards for Assuring Therapeutic Equivalence of Modified Release Products", held October 1–2, 2009, in Baltimore, Maryland. Methods: The workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current regulatory expectations and industry practices for evaluating the pharmaceutical equivalence and bioequivalence of oral MR products. Results: In the case of conventional monophasic MR formulations, the current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and inter-changeability of drug products. Additional measures may occasionally be needed to determine the bioequivalence of multiphasic MR products. The metric of partial AUC proposed by the US Food and Drug Administration received broad support as an additional measure for evaluating bioequivalence of multiphasic MR products designed to have a rapid onset of drug action followed by sustained response. The cutoff for partial AUCs may be based on the pharmacokinetic/pharmacodynamic or pharmacokinetic/ response characteristics of the products under examination. If the new metric is highly variable, the bioequivalence limits may be set based on the known within-subject vari- ability for the reference product. Conclusions: The current regulatory approaches and criteria for bioequivalence evaluation were considered adequate for the assessment of therapeutic equivalence and interchangeability of conventional monophasic MR products. Additional measures may occasionally be needed to establish the bioequivalence of multiphasic MR products, and development of such measures is an important objective. The metric of partial AUC was proposed for products designed to have a rapid drug action followed by sustained response.

Modified release products are complex dosage forms designed to release drug in a controlled manner to achieve desired efficacy and safety. Inappropriate control of drug release from such products may result in reduced efficacy or increased toxicity. This workshop provided an opportunity for pharmaceutical scientists from academia, industry, and regulatory agencies to discuss current industry practices and regulatory expectations for demonstrating pharmaceutical equivalence and bioequivalence of MR products, further facilitating the establishment of regulatory standards for ensuring therapeutic equivalence of these products.

Selective serotonin reuptake inhibitors (SSRIs) may be associated with electrocardiographic effects. The electrocardiographic pharmacodynamics of dapoxetine, a short-acting SSRI being developed for the treatment of premature ejaculation, are compared with those of placebo and moxifloxacin (positive control) in 2 single-center, randomized, crossover studies in healthy men. In study 1, subjects receive 2 doses of dapoxetine 120 mg, given 3 hours apart; a single dose of moxifloxacin 400 mg; and 2 doses of placebo, given 3 hours apart. In study 2, subjects receive single doses of dapoxetine 60 mg, dapoxetine 120 mg, moxifloxacin 400 mg, and placebo. Moxifloxacin significantly increases QT and corrects QT intervals (QTc) compared with placebo in both studies (eg, Bazett-corrected QTc of 11.90 milliseconds [95% confidence interval, 2.68 to 21.11] and 5.06 [95% confidence interval, -2.26 to 12.38]). Dapoxetine 60, 120, and 240 mg do not prolong the QT/QTc interval and have no clinically significant electrocardiographic effects. Dapoxetine and moxifloxacin pharmacokinetics are similar to previous reports. Adverse events are generally mild in severity; nausea is the most common. The results demonstrate that dapoxetine does not have electrocardiographic effects at doses of 60, 120, and 240 mg.

Background: The fentanyl HCl iontophoretic transdermal system (ITS) is a patient-controlled analgesic delivery system that actively administers bolus doses of fentanyl transdermally upon patient activation.Objective: To determine the amount of fentanyl absorbed from fentanyl ITS via passive absorption over a 24.5-h period.Methods: Serial blood samples for pharmacokinetic analyses were obtained from healthy adults who received fentanyl ITS for 24 h. Findings: The average absorption rate was 2.3 µg/h. An average total of 57.4 µg fentanyl was absorbed during the study. The mean maximum observed serum fentanyl concentration was 0.06 ng/mL.Conclusions: Results indicate that the average amount of fentanyl absorbed passively or via passive delivery from fentanyl ITS is minimal. Maximum serum fentanyl concentrations fell below the range associated with analgesia and respiratory depression. The variability in fentanyl exposure was likely exaggerated by the low amounts of drug absorption resulting in overal...

OROS ® (ALZA Corporation, Mountain View, CA, USA) hydromorphone is a unique, once-daily formulation of the potent opioid hydromorphone that is being evaluated for the treatment of moderate-to-severe chronic pain. It uses a patented Push-Pull™ (ALZA Corporation) osmotic pump system to deliver hydromorphone in a continuous, monophasic manner over 24 hours, resulting in minimal peak-trough plasma-level fluctuation. Peak concentrations are achieved approximately 16 hours after administration, with levels equivalent to approximately 80% of peak attained within just 6 hours. The apparent half-life of OROS ® hydromorphone is 7–15 hours and steady-state concentrations are achieved after 2 days of dosing. The pharmacokinetics of OROS ® hydromorphone are dose proportional and are not affected significantly by environmental factors (pH or agitation) or the presence of food. These pharmacokinetic characteristics suggest that OROS ® hydromorphone is well suited to provide consistent, prolonged analgesia in patients with chronic pain.

The osmotic-controlled release oral delivery system, OROS, is an advanced drug delivery technology that uses osmotic pressure as the driving force to deliver pharmacotherapy, usually once-daily, in several therapeutic areas.The purpose of this review is to discuss the evolution of OROS technology and examine the many therapeutic areas where OROS products are being used.A search of Medline and EMBASE were performed using the keywords 'OROS' and 'osmotic delivery' for the period January 1990 to June 2005. Data were also obtained from the manufacturers' websites and associated publications.OROS technology has evolved over the last 30 years, resulting in four systems: the elementary osmotic pump; the two-layer osmotic push-pull tablet; the advanced longitudinally compressed tablet multilayer formulation; and, the L-OROS system. OROS technology is employed for drug delivery in many therapeutic areas including: cardiovascular medicine, endocrinology, urology, and central nervous system (CNS) therapeutics. Two calcium channel blockers utilizing OROS technology for the treatment of hypertension are nifedipine and verapamil. Glipizide extended-release is used for the treatment of type 2 diabetes. Doxazosin is used for the treatment of benign prostatic hyperplasia, and oxybutynin for overactive bladder. Most recent developments are with drugs that affect the CNS, including the use of methylphenidate for treatment of attention deficit hyperactivity disorder, paliperidone extended-release and OROS hydromorphone, which are under clinical development for schizophrenia and chronic pain, respectively.Drug delivery using the various OROS products can result in an improved safety profile, stable drug concentrations, uniform drug effects, and reduced dosing frequency. OROS technology has also enabled the use of an effective starting dose, without the need for dose titration, which allows the achievement of symptom control much earlier than that observed with immediate-release preparations. Such attributes can enhance patient compliance and convenience, thereby ensuring efficacy and improving patient outcomes.

Introduction: The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, needle-free system currently in development for acute pain management in a medically supervised setting. The objectives of these studies were to evaluate skin application sites for the fentanyl HCl PCTS and to evaluate the effect of patient demographics on its pharmacokinetics. Methods: The first study was a randomised, open-label, single-centre, 3-treatment, crossover study in which the fentanyl HCl PCTS was applied to the upper outer arm, lower inner arm or chest of healthy volunteers. Fentanyl 25μg was then delivered via this system twice during the first 20 minutes of every hour for 24 hours. The pharmacokinetics of fentanyl were determined and analysed for each application site using ANOVA. The second study was a nonrandomised, nonblind, multicentre, sequential treatment study. Healthy volunteers received fentanyl HCl 40μg via the PCTS three times during the first 30 minutes of each hour for 3 hours. After a 5- to 10-day washout period, fentanyl HCl 120μg was administered intravenously during the first 30 minutes of each hour for 3 hours as a reference treatment. Pharmacokinetic parameters were determined for the fentanyl HCl PCTS, and results were analysed using ANOVA. Safety and tolerability were evaluated in both studies. Results: Application of the system to the upper outer arm or chest resulted in similar maximum serum concentrations (Cmax; 1.193 and 1.176 μg/L, respectively) and areas under the serum concentration-time curve (AUC24–25; 1.033 and 1.015 μg · h/L). However, both Cmax and AUC24-25 were less when the system was applied to the lower inner arm (0.859 μg/L and 0.757 μg · h/L). Subject age, bodyweight, sex and ethnicity had no significant effect on pharmacokinetic parameters. No serious adverse events were reported in either study during or after administration of the fentanyl HCl PCTS. Conclusion: Fentanyl HCl is comparably absorbed from the PCTS when it is applied to the upper outer arm or chest. The pharmacokinetics of fentanyl HCl delivered by the PCTS are unaffected by sex, age, race or weight.

The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, noninvasive analgesic delivery system for acute pain management. We carried out three studies with the following objectives: study I to evaluate the relationship between fentanyl absorption and the magnitude of current applied to the system; study II to determine dose-proportionality for the fentanyl HCl PCTS (25 and 40 microg); and study III to describe the effects of single- and multiple-day administration on the pharmacokinetics of fentanyl delivered by the PCTS.All studies were open-label, crossover studies with washout periods between treatments. In study I, randomised participants (n = 36) received three of a potential five fentanyl HCl PCTS prototypes, each of which used a different current magnitude, and each of which was evaluated for 24 hours. In study II, participants (n = 40) received fentanyl (25 microg) from the PCTS for 23.33 hours, followed by fentanyl (40 microg) from the PCTS for 23.33 hours. Intravenous (IV) fentanyl (80 microg/h) was administered intermittently over 24 hours as a reference treatment in Studies I and II. In study III, participants (n = 28) received fentanyl (40 microg) from the PCTS for 20 hours, followed by fentanyl (40 microg) from the PCTS for 68 hours. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t(1/2)), were determined for each treatment.The amount of fentanyl absorbed from the PCTS was linearly dependent on the magnitude of current applied to the system, with a current of 170 microA resulting in the absorption of 39.5 microg of fentanyl at hour 23. Mixed-effect ANOVA indicated no significant difference (p0.1) in the dose-normalised pharmacokinetics of the fentanyl HCl PCTS 25 and 40 microg. No significant difference existed between the corrected AUC(0-5) of the fentanyl HCl PCTS during the single- and multiple-day treatment periods (0.40 and 0.54 microg x h/L, respectively; p = 0.133). The system was well tolerated, with headache and mild application site erythema being the most common treatment-related adverse events.A linear relationship exists between the amount of current applied to the fentanyl HCl PCTS and the amount of fentanyl absorbed. There is dose-proportionality in the pharmacokinetics of the fentanyl HCl PCTS 25 and 40 microg. Multiple-day administration does not affect the pharmacokinetics of the fentanyl HCl PCTS 40 microg. The system was well tolerated, even after repeated application.

This study assessed the effect of the proton pump inhibitor omeprazole on the bioavailability of the extended-release formulations of oxybutynin and tolterodine. Forty-four healthy volunteers received each of 4 treatments in a 4-period crossover design. The treatments consisted of osmotically controlled extended-release oxybutynin chloride tablets at 10 mg/d or extended-release tolterodine tartrate capsules at 4 mg/d, with and without preceding treatment with 20 mg omeprazole daily for 4 days. Blood samples collected predose and at scheduled time points for 36 hours postdose were analyzed for oxybutynin and its active metabolite, N-desethyloxybutynin, or tolterodine and its active 5-hydroxymethyl metabolite, as appropriate. The AUCinfinity ratios for oxybutynin and its metabolite with and without prior omeprazole fell within the 80% to 125% range (accepted as the criterion for bioequivalence), as did those for tolterodine and its active moiety. The peak concentration ratios for oxybutynin and metabolite also conformed to this range; those for tolterodine did not. Increasing gastric pH with omeprazole does not substantially alter the pharmacokinetic properties of extended-release oxybutynin but may alter those of extended-release tolterodine.

Aims—To use a nonparametric approach involving longitudinal splines to model the baseline blood pressure profile and investigate the impact of this modelling on the pharmacodynamic analysis for verapamil in patients with angina or hypertension. Methods—Dose ranging studies were conducted in patients with hypertension and with angina. Subjects received doses of 120, 180, 360 or 540mg racemic verapamil. Pharmacodynamic data were created by subtracting the (systolic) blood pressure following active drug from the placebo response, either by direct subtraction or after modelling the baseline with a longitudinal spline model fitted to the placebo data by nonlinear mixed effects modelling. An Emax model was then used to describe the relationship between change in blood pressure and (R-)verapamil plasma concentration. Results—The maximum decrease in systolic blood pressure was found to be 57.6 (±26.1) mm and the C50 was 420 (±349) µg/l for the data obtained by direct subtraction of the placebo data. Similar results were obtained when a cubic spline model was used to describe each individual's placebo response. However, the use of a population spline model only allowed a linear pharmacodynamic model to be fitted to the resulting data. Sparse data were created by randomly removing 66% of the data from the placebo and active phases. The population spline model gave very similar parameter estimates for the linear model applied to the sparse data to those obtained from the complete data set. Conclusions—The use of a longitudinal spline model together with nonlinear mixed effects modelling to account for baseline blood pressure response can be very powerful in a sparse data environment. Copyright © 2004 John Wiley & Sons, Ltd.

This supplement describes a recent development in the use of a drug very familiar to neurologists. The drug is levodopa, which half a century after its introduction is still widely considered the most effective oral agent for treating the motor symptoms of Parkinson disease (PD).1 The recent development is an oral formulation of levodopa plus carbidopa (RYTARY [carbidopa and levodopa] extended-release capsules), a combination of immediate- and extended-release beads with pharmacokinetic properties that produce an initial peak in levodopa plasma levels in about an hour after administration, and maintains them for 4–5 hours before declining.2

Objective Our objective was to determine the effects of age, sex, and sustained-release formulation on apparent oral clearance of sustained-release racemic verapamil in patient populations. Methods Population pharmacokinetic analyses were performed on data from 186 patients with hypertension, coronary artery disease, or supraventricular arrhythmias who were receiving long-term sustained-release oral racemic verapamil (Covera SR in 105 patients, Calan SR in 67 patients, and other formulations in 14 patients; mean ± SD dose, 280 ± 139 mg) for clinical care or as a part of phase III efficacy studies. Of those 186 patients, 135 were men (age, 63 ± 12 years; ideal body weight, 70.7 ± 6.6 kg) and 51 were women (age, 60 ± 17 years; ideal body weight, 53.7 ± 7.2 kg) . Verapamil was measured by HPLC, and population analyses were performed by use of NONMEM software. Sex, age, and formulation were the covariates considered in the population model building. Subgroup analyses of race, smoking, and alcohol consumption were also performed. Significance of covariates was determined by likelihood ratio tests. Results Sex significantly affected steady-state clearance of oral sustained-release racemic verapamil. Apparent oral clearance of sustained-release verapamil was 23.8 ± 2.3 mL/min per kilogram in women compared with 18.6 ± 3.4 mL/min per kilogram in men. Clearance estimates were faster in black subjects compared with white subjects, as well as in smokers compared with nonsmokers. Effects of age, formulation, and alcohol consumption were not detected. Conclusions In middle-aged and older patients, apparent oral clearance of sustained-release racemic verapamil was affected by sex (faster in women compared with men), race (faster in black subjects compared with white subjects), and smoking (faster in smokers compared with nonsmokers) but not by age, alcohol, or formulation. Clinical Pharmacology & Therapeutics (2003) 73, 31–40; doi: 10.1067/mcp.2003.21

The Vertebral Artery (VA) is classically described as originating as the first branch of the ipsilateral subclavian artery. The VA origin is variable and has been identified at the aortic arch, Common Carotid Artery (CCA), and Internal Carotid Artery. The VA arising from the carotid artery is an extremely uncommon variant. Left VA origin from the left CCA has been reported only thrice. These rare anomalous origins of the VA usually are asymptomatic. We describe symptomatic aberrant origin of left vertebral artery from left common carotid artery, a rare case.

Background IPX066, an investigational extended-release carbidopa–levodopa (CD-LD) preparation, has demonstrated a rapid attainment and prolonged maintenance of therapeutic LD plasma concentrations in advanced Parkinson's disease (PD). This phase-3 crossover study assessed its efficacy and safety vs. CD-LD plus entacapone (CL + E). Methods At baseline, all patients had motor fluctuations despite a stable regimen of CL + E or CD-LD-entacapone combination tablets (CLE). The study included a 6-week conversion from CL + E or CLE to IPX066, followed by two 2-week, double-blind crossover treatment periods in randomized order, one on IPX066 (and placebo CL + E), the other on CL + E (and placebo IPX066), separated by 1-week open-label IPX066 treatment. The primary efficacy measure was mean percent daily “off” time during waking hours (from patient diaries). Results Of 91 randomized patients, 84 completed the study. Their median daily LD dosage was 1495 mg from IPX066 and 600 mg from CL + E, corresponding, after correction for bioavailability, to an approximately 22% higher LD exposure on IPX066. Compared with CL + E, IPX066 demonstrated a lower percent “off” time (24.0% vs. 32.5%; p

Aims Dry mouth is a common side-effect seen with immediate-release oxybutynin (IR-Oxy). Ditropan XL®[(Oxy-XL), a controlled-release formulation of oxybutynin chloride, is a once-daily oral dosage form that incorporates the OROS® technology. Dry mouth as the pharmacodynamic measure was compared between Oxy-XL and IR-Oxy administration. The steady state stereospecific pharmacokinetics were also established for the two formulations and the kinetic-dynamic relationship of oxybutynin was examined. Methods This was a randomized, repeated-dose, double-blind, two-treatment, two-period, crossover study. After a baseline assessment day, volunteers were randomly assigned to one of two treatment sequences and received 4 days of each treatment with a washout period of 7 days between treatments. The treatments were: 1) Oxy-XL 10 mg in the morning and placebo 8 h later, and 2) IR-Oxy 5 mg in the morning and again 8 h later. Volunteers assessed dry mouth severity subjectively using a 100 mm visual analogue scale, VAS (Baseline, treatment days 1 and 4) and objectively by collecting saliva (Baseline and treatment day 4) before dosing and every hour after the morning dose for ∼16 h. Several blood samples were collected during each treatment, with frequent sampling on day 4 to analyse for plasma R- and S-oxybutynin and R- and S-desethyloxybutynin concentrations. Results Relatively constant plasma concentrations of oxybutynin and its metabolite were seen over 24 h following Oxy-XL administration with the degree of fluctuation being much lower (P = 0.001; 66% to 81% reduction for the various analytes) than IR-Oxy. Compared with IR-Oxy, Oxy-XL yielded higher (131% and 158% for the R- and S-isomer, respectively) oxybutynin and lower (62% and 78% for the R- and S-isomer, respectively) desethyloxybutynin bioavailability, suggesting reduced first-pass metabolism. Saliva output (area under the effect curve) was significantly higher [P = 0.001; 37% (95% confidence interval: 24, 51%)] with Oxy-XL than with IR-Oxy and, accordingly, dry mouth severity (VAS) integrated over the day was significantly lower with Oxy-XL. The decrease in saliva output and the consequent increase in dry mouth severity correlated with the metabolite R-desethyloxybutynin concentration, and no apparent relationship was observed with the R-oxybutynin concentration. This suggests that the metabolite may contribute to the dry mouth. Therefore, the reduction in metabolite exposure with Oxy-XL may be a possible explanation for the observed decrease in dry mouth severity with OXY-XL compared with IR-Oxy. Conclusions Oxy-XL maintains relatively constant plasma drug and metabolite concentrations and minimizes first-pass metabolism of oxybutynin. The metabolite appears to contribute to dry mouth associated with oxybutynin, and following Oxy-XL metabolite exposure is reduced compared with IR-Oxy. Consequently less dry mouth was observed with Oxy-XL as compared with IR-Oxy.

In vitro–in vivo correlation (IVIVC) models may be used to predict in vivo drug concentration–time profiles given in vitro release characteristics of a drug. This prediction is accomplished by incorporating in vitro release characteristics as an input function ( A vitro ) to a pharmacokinetics model. This simple approach often results in biased predictions of observed in vivo drug concentrations, and it can result in rejecting IVIVC. To solve this problem we propose a population IVIVC model that incorporates the in vitro information and allows one to quantify possibly changed in vivo release characteristic. The model assumes linear kinetics and describes the in vivo release as a sum of A vitro and a nonparametric function ( A d , a spline) representing the difference in release due to in vivo conditions. The function A vitro and its variability enter the model as a prior distribution. The function A d is estimated together with its intersubject variability. The number of parameters associated with A d defines the model: no parameters indicates perfect IVIVC, a large number of parameters indicates poor IVIVC. The number of parameters is determined using statistical model selection criteria. We demonstrate the approach to solve the IVIVC problem of an oral extended release oxybutynin form (OROS), administered in three pharmacokinetic studies. These studies present a particular challenging case; that is, the relative bioavailability for the OROS administration is >100% compared with that of the immediate‐release form. The result of our modeling shows that the apparent lack of IVIVC can be overcome: in vivo concentration can be predicted (within or across data sets) based on in vitro release rate together with a simple form of systematic deviation from the in vitro release . © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:702–712, 2001

Oxybutynin chloride and tolterodine tartrate are anticholinergic agents used to suppress involuntary bladder contractions in urinary incontinence. They act by inhibiting binding of acetylcholine to the muscarinic receptors in the detrusor muscle of the bladder. The same types of muscarinic receptors are found in the salivary glands; thus anticholinergic agents may decrease saliva production and cause dry mouth, a commonly cited reason for discontinuation of therapy.The primary objective of this study was to compare saliva output, which is an objective measure of dry mouth, in subjects taking immediate- or extended-release oxybutynin, tolterodine, or placebo.This was a single-site, single-dose, randomized, double-blind, 4-treatment, 4-period crossover study. Subjects were randomly assigned to 1 of 4 treatment sequences that included extended-release oxybutynin 10 mg, tolterodine 2 mg, immediate-release oxybutynin 5 mg, and placebo. Saliva output was measured objectively before dosing with each treatment and at 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after dosing.Thirty-six healthy adult volunteers (22 women and 14 men) participated in the study. They ranged in age from 19 to 42 years (mean, 27 years). Thirty-one were white, 3 Asian, and 2 black. There were no significant differences in predose saliva output between the 4 study groups. With placebo, saliva output increased throughout the day. Saliva output was maintained at predose levels throughout the day with extended-release oxybutynin. Two hours after dosing with tolterodine and immediate-release oxybutynin, saliva output decreased nearly 0.5 g in specimens collected over 2 minutes. All 3 active treatments were associated with lower saliva output compared with placebo. Extended-release oxybutynin and tolterodine were similar with respect to area under the saliva concentration-time curve but were associated with significantly greater saliva output than was immediate-release oxybutynin (P0.01). There were no serious adverse events (AEs) in this study. AEs were similar between treatments, although the incidence of headache was higher in the active-treatment groups than with placebo.Objective assessment of saliva output in healthy adult volunteers indicated that extended-release oxybutynin and tolterodine had less impact on saliva output than did conventional immediate-release oxybutynin, suggesting that they may yield lower levels of dry mouth.

An in vitro–in vivo correlation (IVIVC) was established for an osmotic controlled-release dosage form by deconvolution using data from an immediate-release treatment as the characteristic response. The established IVIVC was evaluated internally (predicting data used to develop the IVIVC) and externally (predicting data not originally included in developing the IVIVC), and the application of the IVIVC in product development was demonstrated. The estimated in vivo dissolution profile compared favorably with the in vitro drug release profile. Good agreement was demonstrated between the estimated and observed cumulative drug release across the entire time course (level A correlation) with low (

Methylphenidate hydrochloride (HCl) is frequently used for the treatment of attention deficit/hyperactivity disorder (ADHD). A study was conducted in healthy subjects to evaluate the dose-ranging pharmacokinetics of 18, 36, and 54 mg methylphenidate HCl delivered using an oral, osmotic, controlled-release formulation (OROS). Plasma concentrations of l-methylphenidate were 40-fold lower than those of d-methylphenidate, whereas plasma concentrations of d-alpha-phenyl-2-piperidine acetic acid (d-PPA) and l-PPA, the major metabolite of methylphenidate, were comparable. Mean AUCinf values for d-methylphenidate were 42.2, 80.9, and 120 ng.h/mL for the 18, 36, and 54 mg doses, respectively, increasing dose proportionally. AUCinf values for l-methylphenidate were only approximately 1% of d-methylphenidate (0.43, 0.96, and 1.82 ng.h/mL for the 18, 36, and 54 mg dose groups, respectively). In contrast, AUCinf values of d- and l-PPA were comparable. The dose-normalized d- and l-methylphenidate plasma concentration-time profiles for the three treatment groups were superimposable. Similarly, dose-normalized plasma concentrations of d- and l-PPA were superimposable. Methylphenidate metabolism, measured as the ratio of d-methylphenidate AUCinf to d-PPA AUCinf and as l-methylphenidate AUCinf to l-PPA AUCinf, was similar for the three dose groups, indicating that methylphenidate metabolism was not affected by increasing dose. OROS (methylphenidate HCl) exhibits dose-proportional and linear pharmacokinetics.

The total gastrointestinal transit time of nondisintegrating tablets may be affected by dosing time; available literature on this topic is inconclusive. OROS systems are nondisintegrating osmotically driven tablets that release drug over a period of time during their transit through the gastrointestinal tract and are excreted intact in the feces. Total transit times following morning administration of OROS systems pooled from various studies (n = 1,163 systems) showed a distribution with peak frequencies clustering around 24 and 48 h and following night administration (n = 80 systems) was found to cluster around 12 and 36 h. The total transit time distribution appears to be different following morning and night administration. However, on reanalyzing the data considering clock time when the tablet was collected rather than time post-administration, most of the difference between the distribution patterns disappeared. This suggested that total transit times after morning or night administration may be related to the bowel movement habits of the study population. Therefore, OROS systems total transit time were compared to the intrinsic bowel movement pattern of the general population reported in the literature and indeed a good correlation was seen between the two. The total transit time appears to be determined by two factors: the defecation frequency and the probability of its inclusion in the defecation event which is related to its location in the GI tract. A tablet is more likely to be excreted if it is further down in the GI tract. The total transit time data for OROS systems suggest that with the morning dosing the tablet is more likely to be excreted in the bowel movement the next morning. With the night time dosing the tablet may not be far enough in the colon to be excreted in the next morning bowel movement and therefore, it is more likely to be excreted the following morning.

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS (methylphenidate HCl) is an osmotic controlled-release delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS (methylphenidate HCl) 18 mg qd, sustained-release (SR) methylphenidate 20 mg qd, and the immediate-release (IR) formulation given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single- and multiple-dose pharmacokinetics of the OROS formulation were studied. Following OROS (methylphenidate HCl), there was a gradual increase in the mean methylphenidate plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR formulation, peak plasma concentrations were noted at approximately 4 hours. Following the IR regimen, methylphenidate plasma concentrations fluctuated in tandem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half-life of methylphenidate was similar for the three formulations. The dose-normalized methylphenidate Cmax for OROS (methylphenidate HCl) was significantly lower than for IR and SR methylphenidate. The bioavailability of methylphenidate and PPA from OROS (methylphenidate HCl) relative to the IR and SR formulations was complete. Mean methylphenidate AUC and terminal half-life were similar after single (32.9 ng.h/mL and 3.9 hours) and multiple doses (35.2 ng.h/mL and 3.9 hours) of OROS (methylphenidate HCl).

The effects of transdermal iontophoresis (IP) codelivery of hydrocortisone (HC) on metoclopramide hydrochloride (MCP) pharmacokinetics and on skin‐induced reactions were evaluated in a randomized, crossover clinical study. MCP, an antiemetic, low molecular weight, cationic drug intended for systemic delivery, was delivered from the anode of IP systems at a constant current of 100 μA/cm 2 . HC, a neutral endogenous antiinflammatory agent, was codelivered from the same electrode, primarily by electroosmotic processes. Each subject (n = 7) wore two identical IP systems (MCP alone or MCP plus HC), each supplying 500 μA, one on each upper arm for 4 h. One week later, each subject repeated the procedure with the alternate type of MCP system. HC did not change the pharmacokinetics of MCP: There were no statistically significant differences in MCP plasma concentrations, half‐life, area under the curve (AUC), or rate of absorption between the two treatment groups. However, HC significantly decreased erythema and edema scores produced by the IP of MCP. In both groups, a steady‐state MCP flux of about 100 μg/(cm 2 × h) was achieved after only 1 h of transport, and input rate dropped dramatically immediately after removal of the system. In vitro, HC flux through human epidermis from an MCP plus HC formulation was 2.8 ± 1.1 μg/(cm 2 × h) after 4 h transport at 100 μ A/cm 2 , suggesting negligible systemic exposure to hydrocortisone. These data indicate that MCP input rate and its clearance from the skin are unaltered by HC and that the codelivery of HC by IP is an effective strategy for inhibition of local reactions resulting from the transdermal delivery of drugs.

To characterize the pharmacokinetics of amitriptyline and its metabolite nortriptyline following OROS and IR treatments, and to correlate them with anticholinergic side-effects.The pharmacokinetics and safety of amitriptyline following administration of an osmotic controlled release tablet (OROS and an immediate release (IR) tablet were evaluated in 14 healthy subjects. In this randomized, open label, three-way crossover feasibility study, the subjects received a single 75 mg OROS tablet, three 25 mg IR tablets administered every 8 h, or 3x25 mg IR tablets administered at nighttime. In each treatment arm serial blood samples were collected for a period of 84 h after dosing. The plasma samples were analysed by gas chromatography for amitriptyline and its metabolite nortriptyline. Anticholinergic effects such as saliva output, visual acuity, and subject-rated drowsiness and dry mouth were measured on a continuous scale during each treatment period.Following dosing with OROS (amitriptyline hydrochloride), the mean maximal plasma amitriptyline concentration Cmax (15.3 ng ml-1 ) was lower and the mean tmax (25.7 h) was longer than that associated with the equivalent IR dose administered at nighttime (26.8 ng ml-1 and 6.3 h, respectively). The bioavailability of amitriptyline following OROS dosing was 95% relative to IR every 8 h dosing, and 89% relative to IR nighttime dosing. The metabolite-to-drug ratios after the three treatment periods were similar, suggesting no change in metabolism between treatments. The relationships between plasma amitriptyline concentration and anticholinergic effects (e.g. reduced saliva weight, dry mouth, and drowsiness) were similar with all three treatments. Of the anticholinergic effects, only decreased saliva weight and dry mouth correlated well with plasma amitriptyline concentrations; drowsiness did not. There was no apparent correlation between anticholinergic effects and the plasma nortriptyline concentration.The bioavailability of OROS (amitriptyline hydrochloride) was similar to that of the IR treatments and the pharmacokinetics of amitriptyline after OROS dosing may decrease the incidence of anticholinergic effects compared with that seen with nighttime dosing of the IR formulation. Therefore, this controlled-release formulation of amitriptyline may be appropriate for single daily administration.

OROS (melatonin), an oral osmotic system for controlled drug delivery, was evaluated in an open-label, two-way crossover study to test the feasibility of continuous overnight melatonin delivery. Twelve healthy subjects with no sleep disorders, ranging from 60 to 73 years of age, were enrolled in the study. Two doses of melatonin (1 x 110 micrograms and 4 x 110 micrograms) were administered on two separate occasions. Endogenous baseline nighttime serum melatonin concentrations were measured the night before each treatment. Following treatment at 2100 hours, the lights were extinguished at 2200 hours and remained so, except during blood sample collection, which was performed under dim light (< 50 lux) at specified times. Serum samples were analyzed for melatonin by an LC/MS/MS method. In addition, safety measurements such as vitals and serum samples for endocrine functions were measured both prior to and after melatonin dosing. The serum melatonin concentration profile following OROS (melatonin) dosing mimicked the normal endogenous serum melatonin concentration-time profile. The mean maximal melatonin concentration occurred at 3 a.m. The mean AUCs of endogenous melatonin before the two treatment days were 248 and 234 pg.h/mL, respectively. Serum concentrations of melatonin corrected for endogenous production increased proportionally with dose, with AUCs of 288 and 1069 pg.h/mL, respectively. Deconvolution of the serum concentration data showed good correlation between the in vitro amount released and the in vivo amount absorbed, suggesting continuous absorption throughout the gastrointestinal tract. Less than 5% residual content was observed in the recovered OROS system. Minimal changes in serum hormone concentrations (luteinizing hormone, follicular stimulating hormone, and prolactin) and no serious adverse events were observed following OROS treatment in these subjects. Delivery of melatonin with OROS formulation may result in a physiologic nocturnal profile in elderly subjects.

Oxybutynin is used for the treatment of urge urinary incontinence. In this randomized, open-label, two-way crossover, multiple-dose study, the pharmacokinetics of a once-daily, controlled-release formulation, OROS oxybutynin chloride, was compared with that of immediate-release (IR) oxybutynin (Ditropan). Thirteen healthy female volunteers received three 5 mg OROS oxybutynin chloride tablets once daily for 4 days or IR oxybutynin 5 mg administered every 8 hours for 4 days. On day 1, with OROS oxybutynin chloride, mean plasma concentrations rose slowly over approximately 6 hours following dosing (mean Cmax 4.2 ng/mL) and remained fairly constant over the 24-hour dosing interval, whereas with IR oxybutynin, mean plasma concentrations rose rapidly within the first hour after dosing (mean Cmax 12.0 ng/mL), then declined. The mean oxybutynin degree of fluctuation was much lower for OROS oxybutynin chloride (78%) than for IR oxybutynin (371%). For both formulations, the plasma concentration-time profiles for the metabolite N-desethyloxybutynin paralleled those of oxybutynin but at higher concentrations. Steady-state oxybutynin concentrations were achieved by day 3 for both formulations. Mean area under the concentration-time curve (AUC) values for both oxybutynin and its metabolite were similar between day 1 and day 4 for each treatment, suggesting time-invariant pharmacokinetics. With OROS oxybutynin chloride, mean relative bioavailability was higher (153%) for oxybutynin and lower (69%) for N-desethyloxybutynin compared with IR oxybutynin. This increased bioavailability may be due to reduced first-pass metabolism; within 3 to 5 hours after dosing, OROS systems are thought to reach the colon, where cytochrome P450-mediated oxidation (oxybutynin's primary metabolic pathway) may be less extensive than in the small intestine. Fewer subjects reported any adverse event with OROS oxybutynin chloride than with IR oxybutynin (including dry mouth, oxybutynin's most frequently reported anticholinergic adverse effect).

Objectives: (1) To assess the feasibility and tolerability of the therapeutic transdermal fentanyl system (TTS-fentanyl) by using a clinical protocol developed for children with cancer pain. (2) To estimate the pediatric pharmacokinetic parameters of TTS-fentanyl. Methods: The drug was administered in open-label fashion; and measures of analgesia, side effects, and skin changes were obtained for a minimum of 2 doses (6 treatment days). Blood specimens were analyzed for plasma fentanyl concentrations. The pharmacokinetics of TTS-fentanyl were estimated by using a mixed effect modeling approach. Results: Treatment was well tolerated. Ten of the 11 patients who completed the 2 doses continued treatment with TTS-fentanyl. The duration of treatment ranged from 6 to 275 days. The time to reach peak plasma concentration ranged from 18 hours to >66 hours in patients receiving the 25 μg/h patch. Compared with published pharmacokinetic data from adults, the mean clearance and volume of distribution of transdermal fentanyl were the same, but the variability was less. Conclusions: Treatment of children with TTS-fentanyl is feasible and well tolerated and yields fentanyl pharmacokinetic parameter estimates similar to those for adults. A larger study is required to confirm these findings and further test the clinical protocol. (J Pediatr 1999;134:319-23)