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Fosmanogepix (FMGX, APX001), a first-in-class, intravenous (i.v.) and oral (p.o.) antifungal prodrug candidate is currently in clinical development for the treatment of invasive fungal infections. Manogepix (MGX, APX001A), the active moiety of FMGX, interferes with cell wall synthesis by targeting fungal glycosylphosphatidylinositol-anchored cell wall transfer protein 1, thereby causing loss of cell viability.

Objective To evaluate the impact of two calcitonin gene–related peptide (CGRP)‐targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant. Background People taking CGRP‐targeted mAbs for migraine prevention sometimes take ubrogepant, an oral small‐molecule CGRP receptor antagonist, for acute treatment of breakthrough migraine attacks. Design In this two‐arm, multicenter, open‐label, phase 1b trial, adults with migraine were randomized to arm 1 (ubrogepant ± erenumab) or arm 2 (ubrogepant ± galcanezumab). The PK profile of ubrogepant was characterized for administration before and 4 days after CGRP‐targeted mAb injection. Participants received single‐dose ubrogepant 100 mg on day 1, subcutaneous erenumab 140 mg (arm 1) or galcanezumab 240 mg (arm 2) on day 8, and ubrogepant 100 mg once daily on days 12–15. In each study arm, serial blood samples were drawn on days 1 and 12 for measurement of plasma ubrogepant concentrations. The primary outcomes were area under the plasma ubrogepant concentration–time curve (AUC) from time 0 to t post‐dose (AUC0– t) and from time 0 to infinity (AUC0–inf), and maximum plasma concentration (C max) of ubrogepant when ubrogepant was administered before or after a single dose of erenumab or galcanezumab. Vital signs and laboratory parameters were monitored. Results Forty participants enrolled (20 per arm; mean [standard deviation] ages, 32.2 [8.9] and 38.4 [8.8] years; 50% [10/20] and 60% [12/20] female in arms 1 and 2, respectively). There were no significant differences in ubrogepant C max after versus before erenumab administration (geometric least‐squares mean [LSM] ratio, 1.04 [90% CI, 0.93–1.16]), and no significant differences in AUC0– t (1.06 [0.96–1.16]) or AUC0–inf (1.05 [0.96–1.15]). Similarly, ubrogepant C max (1.00 [90% CI, 0.82–1.20]), AUC0– t (1.05 [0.90–1.23]), and AUC0–inf (1.05 [0.90–1.22]) geometric LSM ratios were statistically equivalent after galcanezumab versus ubrogepant alone. Treatment‐emergent adverse events (TEAEs) were similar to those reported with each treatment alone. No serious TEAEs, TEAEs leading to discontinuation, or clinically relevant changes in laboratory parameters or vital signs were reported. Conclusions The PK profile of ubrogepant was not significantly changed and no safety concerns were identified when ubrogepant was coadministered with erenumab or galcanezumab.

Aims Mesalamine is the first-line therapy for treating mild-to-moderate ulcerative colitis. Multiple mesalamine formulations are available, with similar safety and efficacy profiles. Mesalamine is commonly administered as divided dosing, although once-daily dosing may provide benefits for patients. We evaluated the pharmacokinetics of three dosing regimens of two oral delayed-release mesalamine formulations in healthy adult volunteers. Methods A randomised, open-label, parallel-group study of mesalamine pharmacokinetics following Lialda 2 × 1.2 g once daily (QD) (dose A), Asacol 6 × 400 mg QD (dose B), or Asacol 2 × 400 mg three times daily (TID) (dose C) over 7 days. Assessments included 5-aminosalicylic acid (5-ASA) and N-acetyl 5-aminosalicylic acid (N-Ac-5-ASA, primary metabolite) pharmacokinetics (Ae (%), AUC0-24 and Cmax ), safety and tolerability. Results All enrolled volunteers (n = 37) completed the study. Steady state was achieved for all treatments by day 4. Ratios (95% CI) of means for steady-state AUC0-24 (dose A vs B 90.3% [39.8, 204.8], dose A vs C 123.5% [55.3, 275.7], dose B vs C 136.8% [61.3, 305.5]) and Cmax (dose A vs B 106.0% [46.4, 242.2], dose A vs C 133.0% [59.1, 299.0], dose B vs C 125.5% [55.8, 282.1]) were similar for all 5-ASA treatments. Mean urinary excretion of 5-ASA plus N-Ac-5-ASA was comparable between treatments (dose A 21.3%, dose B 20.2%, dose C 17.9%). All treatment regimens were well tolerated; no safety issues were observed. Conclusions Plasma and urine pharmacokinetics for Asacol TID, Asacol QD, and Lialda QD are similar, suggesting similar daily systemic exposures can be obtained with either TID or QD dosing. NCT00751699.

Objective To evaluate the potential for pharmacokinetic interaction and the safety and tolerability when ubrogepant and sumatriptan are coadministered in a Phase 1 study in healthy participants, and to inform the safety and tolerability of ubrogepant alone and in combination with triptans in Phase 3 trials in participants with migraine. Background Calcitonin gene-related peptide is a potent vasodilatory neurotransmitter believed to play a key role in the pathophysiology of migraine. Ubrogepant (UBRELVY™) is a potent and selective antagonist of the human calcitonin gene-related peptide receptor approved for the acute treatment of migraine. Sumatriptan is a serotonin receptor agonist and the most commonly used triptan for the acute treatment of migraine. Ubrogepant could be prescribed with triptans. Design The Phase 1 study was a single-center, open-label, randomized, 3-way crossover, single-dose, pharmacokinetic interaction study, where participants received each of 3 oral treatments with a 7-day washout period between treatments: single dose of ubrogepant 100 mg, single dose of sumatriptan 100 mg, and ubrogepant 100 mg plus sumatriptan 100 mg. Pharmacokinetic parameters were calculated using a model-independent approach. The ACHIEVE I and II trials were 2 multicenter, single-attack, randomized, Phase 3 trials in adults with a history of migraine with or without aura. Participants had the option to take a second dose of study medication or rescue medication to treat a nonresponding migraine or a migraine recurrence from 2 to 48 hours after the initial dose of study medication. Rescue medication options included acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, anti-emetics, or triptans. Treatment-emergent adverse events were evaluated up to 30 days after the last dose in the Phase 1 and Phase 3 studies. Results Ubrogepant median time to maximum plasma concentration was delayed (3 hours [range: 1-5 hours] vs 1.5 hours [range: 1-4 hours]), mean maximum plasma concentration was reduced by 24% (coefficient of variation: 37.4%) when ubrogepant was coadministered with sumatriptan (n = 29) compared with ubrogepant administered alone (N = 30). No significant effect was observed on the area under the plasma concentration-time curve of ubrogepant. Sumatriptan area under the curve and maximum plasma concentration showed no significant change when sumatriptan was coadministered with ubrogepant (n = 29), but the sumatriptan time to maximum plasma concentration was delayed (1 hour [range: 0.5-5 hours] vs 3 hours [range: 0.5-6 hours]. No treatment-emergent adverse events were reported with the coadministration of ubrogepant 100 mg and sumatriptan 100 mg in the Phase 1 study. The pooled safety data from ACHIEVE trials (N = 1938) showed similar rates of treatment-related treatment-emergent adverse events between participants who took ubrogepant alone and participants who took ubrogepant and a triptan as a rescue medication (14.9% [53/355] vs 12.8% [5/39] in the ubrogepant 100 mg treatment group, respectively). Conclusions Although there were slight alterations in ubrogepant pharmacokinetic parameters when coadministered with sumatriptan, such changes are expected to have minimal clinical relevance, especially because no changes were seen in sumatriptan area under the curve and maximum plasma concentration when coadministered with ubrogepant. Coadministration of ubrogepant with sumatriptan was well tolerated in healthy participants in the Phase 1 study, and coadministration of ubrogepant with triptans was well tolerated in participants with migraine in the Phase 3 trials. No new safety concerns for ubrogepant were identified across all trials.

Ubrogepant is a novel, oral calcitonin gene-related peptide (CGRP) receptor antagonist intended for the acute treatment of migraine attacks. Ubrogepant has a chemical structure distinct from previous small-molecule CGRP receptor antagonists that were associated with elevated serum alanine aminotransferase (ALT) in clinical trials. Here, we report overall and hepatic safety data from two placebo-controlled phase I trials of ubrogepant, spray-dried oral compressed tablet (SD-OCT) in healthy male volunteers. Trial A was a pharmacokinetic (PK) trial of single (100-400 mg) and multiple (40-400 mg) ascending doses. Trial B was a dedicated hepatic safety trial assessing daily use of ubrogepant 150 mg for 28 days. Serum ALT (as hepatotoxicity biomarker) and PK data are reported. Ubrogepant was well-tolerated in both trials, with a low incidence of adverse events that did not differ greatly from placebo. Changes in mean ALT levels were minimal and similar to placebo. Over 28 days of treatment, the mean percentage change in ALT from baseline was < 5% at all time points. No participant in either trial demonstrated ALT ≥ 3× upper limit of normal at any time. Ubrogepant SD-OCT demonstrated linear PK appropriate for acute treatment of migraine, with rapid uptake (time of maximum plasma concentration (tmax ): 2-3 hours) and no accumulation with daily use. Overall, there was no evidence of ubrogepant-associated hepatotoxicity with daily doses up to 400 mg for 10 days or with daily ubrogepant 150 mg for 28 days. Supratherapeutic dosing is a useful strategy for characterizing hepatic safety in early drug development.

Ubrogepant is a novel, oral calcitonin gene-related peptide receptor antagonist currently under US Food and Drug Administration (FDA) review for the acute treatment of migraine attacks. This double-blind, four-period crossover study compared the cardiac repolarization effect of therapeutic (100 mg) and supratherapeutic (400 mg) ubrogepant doses vs. placebo in healthy adults. Moxifloxacin 400 mg was used as an open-label active control, and the primary end point was change from baseline in Fridericia-corrected QT intervals (ΔQTcF). Assay sensitivity was demonstrated via statistically significant QTcF prolongation with moxifloxacin vs. placebo. After single oral doses of ubrogepant, the least squares mean placebo-corrected ΔQTcF (ΔΔQTcF) and 90% confidence intervals (CIs) did not exceed the 10-millisecond regulatory threshold at any timepoint. The 90% CI upper bounds were 2.46 milliseconds and 2.69 milliseconds for ubrogepant 100 and 400 mg, respectively. Categorical and concentration-based analyses were consistent with the primary result, showing no significant impact of ubrogepant on cardiac repolarization.

Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.

Background Ubrogepant is a novel, oral calcitonin gene–related peptide (CGRP) receptor antagonist in development for the acute treatment of migraine. This trial evaluated the safety and tolerability of ubrogepant, focusing on hepatic safety, when administered intermittently with high-frequency dosing to healthy participants. Methods In this phase 1, multicenter, double-blind, parallel-group trial, healthy adults (age 18–50 years) were randomized 1:1 to placebo or ubrogepant. Ubrogepant was dosed at 100 mg (2 × 50 mg tablets) on 2 consecutive days followed by 2 consecutive days of placebo, alternating for 8 weeks. Primary outcome measures were safety and tolerability. Results Of participants randomized (n = 518), 516 were included in the safety population (n = 260 placebo; n = 256 ubrogepant). Treatment-emergent adverse events were reported in 45% of placebo and 44% of ubrogepant participants. The most common was headache (10% placebo; 11% ubrogepant). Overall, seven cases of alanine aminotransferase and/or aspartate aminotransferase levels ≥ 3 × the upper limit of normal (five placebo, two ubrogepant) were reported and adjudicated by a panel of independent liver experts blinded to treatment. Four cases were judged unlikely related to treatment. Two cases (one placebo, one ubrogepant) were judged possibly related, and one (ubrogepant) probably related. Alanine aminotransferase increases to ≥ 3 × the upper limit of normal in the two ubrogepant cases (possibly or probably related) were transient and resolved with continued dosing; both cases were asymptomatic, with no concurrent bilirubin elevation. Conclusion Ubrogepant was well tolerated following intermittent, high-frequency dosing in healthy participants, with no clinically relevant signal of hepatotoxicity. Trial Registration NA.

Objective: Delayed-release mesalamine 400 mg capsules containing four 100 mg tablets have been developed for children with ulcerative colitis who have difficulty swallowing. Bioavailability of the mesalamine capsules was compared with existing mesalamine tablets in healthy adults, and the effect of food on bioavailability from mesalamine capsules was determined. Tablet swallowability in healthy children was evaluated. Methods: In the open-label, replicate-treatment, single-dose, crossover, comparative bioavailability study, healthy adult volunteers were randomized to one of four treatment sequences to receive mesalamine 400 mg tablets (fasted) twice, mesalamine 400 mg capsules (fasted) twice, and a mesalamine 400 mg capsule (with food) once, with ≥7 days between treatments. Pharmacokinetic (PK) parameters were calculated and analyzed using the reference-scaled average bioequivalence procedure. In the open-label, single-dose swallowability study, healthy children aged 5-11 years were asked to swallow eight placebo tablets identical to those contained in two mesalamine capsules. Results: In the bioavailability study (n=160), mesalamine capsules and tablets in fasted volunteers exhibited similarly delayed absorption and were shown to be bioequivalent; statistical parameters calculated from PK values met the criteria for bioequivalence. A slight increase in mesalamine bioavailability was observed with food administration, but the delayed-release performance of the capsules was not affected. Overall safety profiles between capsules and tablets were similar. In the swallowability study (n=60), the majority of children swallowed eight placebo tablets, with slight variability between age groups. Conclusion: Evaluation of PK parameters confirmed mesalamine capsules are bioequivalent to mesalamine tablets. Mesalamine capsules were well tolerated, can be administered with or without food, and are an age-appropriate product for children.

Atogepant is a selective oral calcitonin gene‐related peptide receptor antagonist in development for migraine prevention. Here, we report the pharmacokinetics (PK) and safety of single‐dose 60 mg atogepant in participants with severe, moderate, or mild hepatic impairment and matched participants with normal hepatic function from an open‐label, parallel‐group, single‐dose phase 1 trial. Thirty‐two participants aged 45 to 72 years were enrolled, which included 8 each with severe, moderate, mild, or no hepatic impairment. All participants completed the study. Atogepant was rapidly absorbed (median time to maximum plasma concentration, ∼2 hours) with an apparent terminal elimination half‐life of ∼11 hours. Compared with participants with normal hepatic function, the change in maximum plasma concentrations of atogepant were –4%, –12%, and +9% in participants with severe, moderate, or mild hepatic impairment, respectively. Overall systemic exposures to atogepant were 15% to 38% higher in participants with hepatic impairment compared with those with normal hepatic function, but these differences are not expected to be clinically relevant given the established safety profile of atogepant. Only 1 adverse event was reported: mild rhinorrhea in a participant with moderate hepatic impairment. Overall, atogepant was safe and not associated with any clinically relevant change in PK in participants with severe, moderate, or mild hepatic impairment.

Supplemental material, sj-pdf-3-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-10-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-5-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental Material, Jakate-et-al_SUPPLEMENTAL-MATERIAL-FOR-SUBMISSION for Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial by Abhijeet Jakate, Ramesh Boinpally, Matthew Butler, Kaifeng Lu, Kristi Womack, Danielle McGeeney and Antonia Periclou in Cephalalgia Reports

Supplemental material, sj-pdf-9-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-6-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-4-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-2-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-8-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

Supplemental material, sj-pdf-7-cep-10.1177_0333102420970523 for Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications by Peter J Goadsby, Andrew M Blumenfeld, Richard B Lipton, David W Dodick, Kavita Kalidas, Aubrey M Adams, Abhijeet Jakate, Chengcheng Liu, Armin Szegedi and Joel M Trugman in Cephalalgia

To treat hypertension, combining two or more antihypertensive drugs from different classes is often necessary. β-Blockers and renin-angiotensin-aldosterone system inhibitors, when combined, have been deemed 'less effective' based on partially overlapping mechanisms of action and limited evidence. Recently, the single-pill combination (SPC) of nebivolol (Neb) 5 mg - a vasodilatory β1-selective antagonist/β3 agonist - and valsartan 80 mg, an angiotensin II receptor blocker, was US Food and Drug Administration-approved for hypertension. Pharmacological profiles of Neb and valsartan, alone and combined, are well characterized. In addition, a large 8-week randomized trial in stages I-II hypertensive patients (N = 4161) demonstrated greater blood pressure-reducing efficacy for Neb/valsartan SPCs than component monotherapies with comparable tolerability. In a biomarkers substudy (N = 805), Neb/valsartan SPCs prevented valsartan-induced increases in plasma renin, and a greater reduction in plasma aldosterone was observed with the highest SPC dose vs. valsartan 320 mg/day. This review summarizes preclinical and clinical evidence supporting Neb/valsartan as an efficacious and well tolerated combination treatment for hypertension.

Objective: Delayed-release mesalamine 400 mg capsules containing four 100 mg tablets have been developed for children with ulcerative colitis who have difficulty swallowing. Bioavailability of the mesalamine capsules was compared with existing mesalamine tablets in healthy adults, and the effect of food on bioavailability from mesalamine capsules was determined. Tablet swallowability in healthy children was evaluated. Methods: In the open-label, replicate-treatment, single-dose, crossover, comparative bioavailability study, healthy adult volunteers were randomized to one of four treatment sequences to receive mesalamine 400 mg tablets (fasted) twice, mesalamine 400 mg capsules (fasted) twice, and a mesalamine 400 mg capsule (with food) once, with ≥7 days between treatments. Pharmacokinetic (PK) parameters were calculated and analyzed using the reference-scaled average bioequivalence procedure. In the open-label, single-dose swallowability study, healthy children aged 5–11 years were asked to swallow eight placebo tablets identical to those contained in two mesalamine capsules. Results: In the bioavailability study (n=160), mesalamine capsules and tablets in fasted volunteers exhibited similarly delayed absorption and were shown to be bioequivalent; statistical parameters calculated from PK values met the criteria for bioequivalence. A slight increase in mesalamine bioavailability was observed with food administration, but the delayed-release performance of the capsules was not affected. Overall safety profiles between capsules and tablets were similar. In the swallowability study (n=60), the majority of children swallowed eight placebo tablets, with slight variability between age groups. Conclusion: Evaluation of PK parameters confirmed mesalamine capsules are bioequivalent to mesalamine tablets. Mesalamine capsules were well tolerated, can be administered with or without food, and are an age-appropriate product for children.

Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist for acute treatment of migraine. This study evaluated potential drug–drug interactions between ubrogepant and an oral contraceptive containing ethinyl estradiol (EE) and norgestimate (NGM). Methods: This open-label, single-center, two-period, fixed-sequence study enrolled healthy, postmenopausal or oophorectomized, adult women. In period 1, participants received a single oral dose of EE 0.035 mg/NGM 0.25 mg (EE-NGM) followed by a 7-day washout. In period 2, participants received oral ubrogepant 50 mg daily on days 1–14; single-dose EE-NGM was coadministered with ubrogepant on day 10. Pharmacokinetic parameters for plasma EE and norelgestromin (NGMN) were compared with and without ubrogepant. Results: Twenty-two participants aged 46–66 years were enrolled; 21 completed the study. Geometric mean ratios and 90% confidence intervals for the comparison of EE-NGM + ubrogepant to EE-NGM alone were contained within 0.80 and 1.25 for area under the plasma drug concentration–time curve (AUC) from time zero to infinity (AUC0–∞; 0.96 [0.91, 1.01]) and C max (0.91 [0.82, 1.004]) of NGMN and AUC0–∞ (0.97 [0.93, 1.01]) of EE, but not C max of EE (0.74 [0.69, 0.79]). Median t max of EE was delayed following EE-NGM + ubrogepant (3.0 h) versus EE-NGM alone (median of 1.5 h), whereas median t max of NGMN was unchanged (1.5 h). Geometric mean apparent terminal half-life ( t ½) was similar with and without ubrogepant for EE (23 vs. 21 h) and NGMN (36 h both conditions). All ubrogepant-related adverse events were mild or moderate. Conclusion: Ubrogepant did not demonstrate potential for clinically meaningful drug–drug interactions with an EE-NGM oral contraceptive. Trial registration: Not applicable (phase 1 trial)

Peter Dogterom,1 Robert Riesenberg,2 Rik de Greef,1 Justin Dennie,3 Martin Johnson,1 Venkatesh Pilla Reddy,1 André MM Miltenburg,1 Robert L Findling,4 Abhijeet Jakate,5 Timothy J Carrothers,5 Matthew D Troyer3 1Early Stage Development, Merck Sharp and Dohme, Oss, the Netherlands; 2Atlanta Center for Medical Research, Atlanta, GA, 3Merck, Kenilworth, NJ, 4Kennedy Krieger Institute, Johns Hopkins University, Baltimore, MD, 5Allergan, Madison, NJ, USA Purpose: This study aimed to characterize the pharmacokinetic (PK) properties, safety, and tolerability of asenapine, and to develop a population PK model in pediatric patients with schizophrenia, bipolar disorder, or other psychiatric disorders. Methods: Two Phase I multiple ascending-dose studies were conducted to evaluate the PK, safety, and tolerability of sublingual asenapine in pediatric patients (age 10–17 years) with schizophrenia or bipolar I disorder. Patients received asenapine 1–10 mg twice daily for up to 12 days. PK parameters (maximum concentration [Cmax], area under the curve from 0 to 12 hours [AUC0–12], time to Cmax [Tmax], and half-life) were summarized for asenapine with descriptive statistics, and safety parameters were collected. A population PK model, which included the two Phase I studies and two additional Phase III efficacy studies (asenapine 2.5–10 mg twice daily for up to 8 weeks, age 10–17 years), was developed using nonlinear mixed-effect modeling based on a previously developed adult PK model. The final model was used in simulations to obtain asenapine-exposure estimates across pediatric subgroups and to determine if intrinsic covariates warrant dose adjustments. Results: The PK of asenapine showed rapid absorption (Tmax ~1 hour) with an apparent terminal half-life between 16 and 32 hours. Increases in mean Cmax and AUC0–12 appeared to be dose-proportional in one study and near dose-proportional in the second study. Steady state was attained within 8 days. The most frequently occurring treatment-emergent adverse events were dysgeusia, sedation, and oral hypoesthesia. Simulation-based estimates of Cmax and AUC0–12 were similar for pediatric and adult patients; age, body-mass index, race, and sex were not associated with changes in asenapine exposure. Conclusion: Asenapine was generally safe and well tolerated in pediatric patients aged 10–17 years. PK and safety data were similar to that observed in the adult population. Intrinsic factors had no significant impact on asenapine exposure, indicating there is no need for dose adjustments in the pediatric population. Keywords: asenapine, pharmacokinetics, schizophrenia, bipolar disorder, child and adolescent, atypical antipsychotic

Ceftaroline fosamil is a parenteral cephalosporin indicated for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Ceftaroline, the active component of ceftaroline fosamil, exhibits broad-spectrum bactericidal activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common gram-negative pathogens. The objective of the studies presented herein was to establish the pharmacokinetic profile of ceftaroline in healthy subjects and special populations of interest, such as elderly subjects, subjects with renal impairment, or subjects with end-stage renal disease on intermittent hemodialysis. The mean half-life of ceftaroline in healthy subjects was approximately 2.6 hours, and urinary excretion was the primary route of elimination. Ceftaroline Cmax and AUC values increased in proportion to dose increases within the range of 50-1000 mg, demonstrating an approximately linear pharmacokinetic profile following intravenous infusion. The pharmacokinetic parameters of ceftaroline were modestly altered in elderly subjects compared with younger adults, which was attributed to decreased renal function in elderly subjects. Ceftaroline pharmacokinetic parameters varied with different degrees of renal impairment, resulting in recommended dosage adjustments for patients with moderate to severe impairment. Ceftaroline fosamil was generally well tolerated regardless of age or severity of renal impairment.

Dexloxiglumide is a potent and selective cholecystokinin type 1 (CCK1) receptor antagonist currently under development in a variety of diseases affecting the gastrointestinal tract such as gastro-oesophageal reflux disease, irritable bowel syndrome (IBS), functional dyspepsia, constipation and gastric emptying disorders. In female patients with constipation-predominant IBS, clinical efficacy has been demonstrated following administration of dexloxiglumide 200 mg three times daily. Dexloxiglumide is rapidly and extensively absorbed after single oral administration in humans with an absolute bioavailability of 48%. The incomplete bioavailability is due to both incomplete absorption and hepatic first-pass effect. Following multiple-dose administration of 200 mg three times daily, the accumulation is predictable, indicating time-independent pharmacokinetics. In addition, dexloxiglumide pharmacokinetics are dose-independent after both single and repeated oral three-times-daily doses in the dose range 100-400 mg. Dexloxiglumide absorption window extends from the jejunum to the colon and the drug is a substrate and a weak inhibitor of P-glycoprotein and multidrug resistance protein 1. Plasma protein binding of dexloxiglumide is 94-98% and the drug has a moderate to low volume of distribution in humans. Systemic clearance of dexloxiglumide is moderate and cytochrome P450 (CYP) 3A4/5 and CYP2C9 have been implicated in the metabolism of dexloxiglumide to produce O-demethyl dexloxi-glumide. This metabolite is further oxidised to dexloxiglumide carboxylic acid. These two major metabolites (accounting for up to 50% of dexloxiglumide elimination) have been identified. However, in human plasma the unchanged drug represents the major (up to 91%) component of the metabolic profile. The parent drug is believed to be the major contributor to the efficacy of the compound, since its major metabolites are pharmacologically inactive. In addition, the drug is a single isomer chiral drug (eutomer) that does not undergo chiral inversion into its pharmacologically inactive enantiomer (distomer). After oral administration of (14)C-dexloxiglumide, radioactivity is mainly excreted in bile and in faeces (74% of dose) with much lower excretion in urine (20% of dose). Renal excretion of unchanged dexloxiglumide is low (7% of dose in urine and faeces, 1% of dose in urine) and is dose-independent in the dose range 100-400 mg. As the kidney is a minor contributor to the elimination of dexloxiglumide and/or its metabolites in humans, the pharmacokinetics of the drug should not be affected in patients with renal insufficiency. The pharmacokinetics of dexloxiglumide are also not affected by age, sex and administration with a high-fat breakfast. Mild and moderate liver impairment do not affect the pharmacokinetics of dexloxiglumide but severe liver impairment causes increases in systemic exposure to dexloxiglumide and O-demethyl dexloxiglumide. Thus, the drug should be prescribed with caution in patients with severe hepatic impairment even though no dose adjustment is warranted. The results of different drug interaction studies have indicated that no clinically relevant metabolic and concomitant drug-drug interactions are expected during the clinical use of dexloxiglumide.

Aims Dexloxiglumide is a new CCK1 receptor antagonist under investigation for treatment of functional gastrointestinal disorders and is metabolized by CYP3A4 and CYP2C9. The objectives of these two separate randomized, two-period, two-treatment crossover studies were to investigate the effects of steady-state ketoconazole, a model CYP3A4 inhibitor (Study 1), and steady-state fluconazole, a model CYP2C9 inhibitor (Study 2), on the pharmacokinetics of dexloxiglumide in healthy subjects. Methods Plasma samples were analysed for dexloxiglumide and its primary metabolites: O-demethyl dexloxiglumide (ODM; Study 1 and 2) and dexloxiglumide carboxylic acid (DCA; Study 2). Results Following ketoconazole coadministration, dexloxiglumide Cmax increased by 32% (90% confidence intervals (CI) 112–154), with unchanged ODM Cmax; AUC of dexloxiglumide and ODM increased by 36% (90% CI 124–140 and 128–142, respectively). No changes were observed in dexloxiglumide or ODM t½. Fluconazole coadministration caused a 77% increase (90% CI 154–204) in dexloxiglumide Cmax, no change in ODM Cmax and a 32% decrease (90% CI 62–75) in DCA Cmax. Fluconazole coadministration resulted in a 2.5-fold increase (90% CI 235–267) in dexloxiglumide AUC, 40% increase (90% CI 136–156) in ODM AUC and an 18% decrease (90% CI 82–94) in DCA AUC. The t½ of all three analytes increased by approximately 2-fold with fluconazole coadministration (P-value

This study was undertaken to evaluate the effect of dexloxiglumide, a selective cholecystokinin receptor antagonist, on the pharmacokinetics of a combination oral contraceptive (OC). A single-blind, placebo-controlled, 2-period crossover study was conducted in 24 healthy young female subjects who received Ortho Tri-Cyclen containing ethinyl estradiol (EE, 0.035 mg) and norgestimate (NE, 0.180 mg/ 0.215 mg/0.250 mg per 7-day phase, respectively) for 5 days (days 17-21) concurrently with either 200 mg dexloxiglumide (3 times a day on days 17-20, followed by a single dose on day 21) or matching placebo during 2 consecutive 28-day OC dosing cycles. Plasma was sampled up to 24 hours for the determination of EE, NE, and 17-deactyl norgestimate (1 7-DNE, a rapidly formed pharmacologically active metabolite of NE). The geometric mean ratios (GMRs, dexloxiglumide/placebo) of the plasma concentration-time curve over 24 hours with corresponding 90% confidence intervals (CIs) for EE and 17-DNE were 1.21 (1.17-1.26) and 0.92 (0.89-0.95), respectively. The GMRs (90% CI) of C m a x for EE and 17-DNE were 1.15 (1.09-1.20) and 0.93 (0.90-0.96), respectively. Coadministration of OC and dexloxiglumide was well tolerated and safe. Comparable systemic exposure of EE and 17-DNE in the presence and absence of dexloxiglumide suggests that dexloxiglumide treatment is unlikely to interfere with the safety and efficacy of oral contraceptives based on the analysis of the resulting pharmacokinetic profile.

Ceftaroline fosamil is a parenteral cephalosporin indicated for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Ceftaroline, the active component of ceftaroline fosamil, exhibits broad-spectrum bactericidal activity against gram-positive organisms, including methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae, as well as common gram-negative pathogens. The objective of the studies presented herein was to establish the pharmacokinetic profile of ceftaroline in healthy subjects and special populations of interest, such as elderly subjects, subjects with renal impairment, or subjects with end-stage renal disease on intermittent hemodialysis. The mean half-life of ceftaroline in healthy subjects was approximately 2.6 hours, and urinary excretion was the primary route of elimination. Ceftaroline Cmax and AUC values increased in proportion to dose increases within the range of 50-1000 mg, demonstrating an approximately linear pharmacokinetic profile following intravenous infusion. The pharmacokinetic parameters of ceftaroline were modestly altered in elderly subjects compared with younger adults, which was attributed to decreased renal function in elderly subjects. Ceftaroline pharmacokinetic parameters varied with different degrees of renal impairment, resulting in recommended dosage adjustments for patients with moderate to severe impairment. Ceftaroline fosamil was generally well tolerated regardless of age or severity of renal impairment.