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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 (

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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).

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).

This open-label, parallel study of 28 men was conducted to evaluate the pharmacokinetics and safety of fentanyl delivered by the E-TRANS (fentanyl) electrotransport transdermal system (ALZA Corporation, Palo Alto, CA). The E-TRANS (fentanyl) system provided electrically assisted, transdermal, continuous delivery of fentanyl. Treatments consisted of no current (group A); a constant current of 100 microA for 26 hours plus 4 additional doses at varying currents for varying times during hour 25 (groups B, C, D); a constant current of 100 microA for 26 hours plus 4 additional doses at 1,200 microA over 2.5 minutes during hour 1 (group E); or 500 microA for 0.5 hours and 100 microA for 3.5 hours (group F). No fentanyl was detected in serum when no current had been applied. Mean serum fentanyl concentrations were similar regardless of current duration during hour 25 (treatments B, C, D). Increases in mean serum fentanyl concentrations were significantly lower during additional dosing for treatment E compared with treatments B, C, and D. Serum fentanyl concentrations sufficient for analgesia (1-3 ng/mL) were attained in treatments using the E-TRANS (fentanyl) system with basal current of 100 microA for 26 hours. There were no safety issues after treatment with E-TRANS (fentanyl) system with concurrent opioid antagonist (naltrexone) administration. The only adverse event requiring treatment was a headache (n = 1). The majority of subjects had no or barely perceptible erythema at the application site 24 hours after system removal. Application of E-TRANS (fentanyl) resulted in therapeutically significant serum fentanyl concentrations over a range of applied currents. Overall serum fentanyl concentrations were higher when the skin had been primed by constant-current fentanyl delivery.

A model for the pharmacodynamic effect of a drug (designated only X), and the use of the model to explore optimal input is described. The data analyzed here are from a crossover comparison study of the effect of 4 active treatments, yielding distinct concentration vs. time curves, plus placebo in 32 subjects. The model expresses total effect as the sum of placebo effect and (pure) drug effect. The latter allows for possible tolerance (found) and time effects (not found). Random effects allow interindividual differences to be expressed. Conditioning on the fitted model, a population optimal input profile is designed that obeys certain protocol constraints. The profile minimizes the expectation of a sum of squared differences between target effect and the resulting response over a given time interval. The target is a fixed constant, chosen to be either the individuals' maximum effect level in response to a baseline input regimen used in the study or the maximum effect level for the typical individual in the population in response to this regimen, as predicted from the model. The expectation is taken over the estimated nonparametric distribution of the 32 subjects' random effects. As one goal of early clinical studies of drugs may be to provide a basis for designing an optimal delivery profile (with respect to a specified loss function), we suggest this report as an example of a reasonable way to go about finding such a profile.

This open-label, randomized, placebo lead-in, three-treatment crossover study in 19 hypogonadal men (27-82 years of age) evaluated dose proportionality of serum testosterone concentrations with application of one or two investigational transdermal testosterone systems for application to the arm or torso. Testosterone in vivo kinetics profiles were determined using DeMonS, a recently developed numerical deconvolution method that estimates drug absorption at different time intervals and/or drug disposition model parameters. After application of the investigational transdermal systems, the mean serum testosterone, dihydrotestosterone, estradiol, and free testosterone concentrations were elevated to normal levels. Treatment allowed approximation of the normal circadian pattern of endogenous testosterone secretion, and the increase in serum testosterone concentrations was proportional to the surface area of systems applied. The investigational transdermal system provided effective testosterone replacement therapy as judged by pharmacokinetic parameters.

In this study of 13 hypogonadal men (25-69 years of age), three open-label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration-time curve from 0 to 27 hours (AUC0-27) values for testosterone after one-day applications to the upper buttocks, upper arm, and back were 9,560 ng.hr/dL, 8,651 ng.hr/dL, and 8,988 ng.hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days.

DeMonS—a new numerical deconvolution method for estimating the amount of drug absorbed at different time intervals and/or drug disposition model parameters—is presented here. In DeMonS, the amount of drug absorbed at different time intervals and/or drug disposition model parameters are the unknown parameters to be calculated. The Fritsch–Butland non-decreasing cubic spline was constructed from the cumulative amount of drug absorbed–time data directly derived from the calculated amount of drug absorbed at different time intervals. The drug absorption rate, which is the derivative of this non-decreasing cubic spline, is therefore represented by a piecewise non-negative quadratic function. The drug concentrations were obtained by convoluting the drug absorption rate quadratic function with the drug disposition model function. The nonlinear optimization method with simple parameter bounds was used to estimate the optimal set of unknown parameters by minimizing the sum of squares of residuals between the observed and predicted drug concentrations. DeMonS has been applied to (i) the griseofulvin data for estimating drug absorbed at different time intervals when the drug disposition model parameters were determined separately from intravenous data, (ii) veralipride double-peak phenomenon data to estimate simultaneously the percentage of cumulative veralipride absorbed and the veralipride disposition model parameters without reference intravenous data, (iii) a comparative bioequivalence study of gastrointestinal therapeutic system (GITS) pseudoephedrine HCI (PeHCI) controlled-release oral dosage forms when the drug disposition model parameters were not available, and (iv) estimation of both drug disposition model parameters and the absorption rate of drug from Testoderm® (testosterone transdermal system) in the presence of endogenous testosterone production. DeMonS was implemented using MATLAB® and NAG® MATLAB Toolbox, and is available for Windows 3.1. © 1997 John Wiley & Sons, Ltd.

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. Cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37 degrees C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high-performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen-induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0-10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect.

Nicoderm, a nicotine transdermal system (NTS), provides a continuous, transdermal delivery of nicotine and is used as an aid to smoking cessation. In contrast, cigarette smoking yields nicotine concentrations in plasma that rise and fall with each cigarette. The primary objective of this study was to compare nicotine pharmacokinetics after treatment of subjects with either the NTS or controlled smoking. Fourteen healthy adult male smokers, who smoked at least 30 cigarettes per day, were entered into a randomized crossover design trial that compared the NTS, 21 mg/day applied for 24 hours, with half-hourly smoking during the day. Subjects abstained from smoking for 2 days, and were treated for 5 days with either the NTS (daily) or controlled smoking (30 cigarettes at half-hourly intervals on days 1 and 5; ad libitum smoking on days 2-4). Blood samples were obtained frequently on days 1 and 5 for analysis of nicotine and cotinine. Pharmacokinetic comparisons showed that nicotine Cmax, area under the curve (AUC)inf, and Cavg for the NTS were lower than corresponding values for controlled smoking; Cmax and Cavg values were approximately half those of smoking. Cmax and Cavg values for cotinine were similarly lower for the NTS compared to controlled smoking. For both treatments, plasma nicotine concentrations were higher on day 5 compared to day 1. Thus, the NTS provides concentrations of nicotine that are lower than smoking.

1. Pharmacokinetics and pharmacodynamics of R- and S-verapamil and R- and S-norverapamil were studied at steady state following administration of 180 mg verapamil delivered by a controlled-release gastrointestinal therapeutic system (COER-verapamil). 2. Of the 30 young (19 to 43 years) and 30 elderly subjects (65 to 80 years) enrolled, approximately half of each age group were women; all subjects were healthy and none were smokers. 3. Mean R- and S-verapamil and R- and S-norverapamil Cmax, Cmin, and AUC values for elderly subjects were 1.2 to 2.2 times greater than those for young subjects; these differences were statistically significant at P < 0.05. Median tmax values for young and elderly subjects were not significantly different for any enantiomer. The mean half-life values of R- and S-verapamil for elderly subjects were approximately 20 h compared with approximately 13 h for young subjects, respectively. The mean half-life values of R- and S-norverapamil for elderly subjects were approximately 31 h and 20 h, respectively, compared with approximately 19 h and 21 h for young subjects, respectively. 4. In both age groups, the mean plasma verapamil concentrations of each enantiomer were higher for women than for men at all time points. 5. Mean arterial pressure (MAP) had a significant correlation to R- (r2 = 0.86) and S-verapamil (r2 = 0.87) concentration values that was not influenced by either gender or age of the patient. Change in PR-interval also had a significant correlation to R- and S-verapamil concentration values. However, the sensitivity of the response to changes in R- and S-verapamil concentration values in elderly subjects was about 1/5 of that in younger subjects.

Parkinson’s disease (PD) is a progressive neurodegenerative disease that affects approximately 1–2% of the population above 60 years of age.1 The cardinal clinical manifestations of PD are resting tremor, rigidity, bradykinesia, and gait dysfunction. During the early stages of the disease, about 70% of patients may experience a slight tremor. Bradykinesia is described as a general reduction in spontaneous movement, and can cause difficulty with repetitive movements, such as finger tapping. Rigidity may cause stiffness of the limbs, neck, and trunk and may affect walking. The Unified Parkinson’s disease rating scale (UPDRS) is a scale developed by the Movement Disorders Society Task Force on Rating Scales for Parkinson’s Disease.2 This scale provides an efficient and flexible means of monitoring PD-related disability and impairment, and has been used in studies of early, mild, moderate, and advanced disease with motor fluctuations. The total UPDRS scale comprises four components: Part I, Mentation, Behavior, and Mood; Part II, Activities of Daily Living; Part III, Motor; Part IV, Complications of therapy. Levodopa (LD), combined with a dopa decarboxylase inhibitor such as carbidopa (CD) or benserazide, continues to be an important mainstay in the symptomatic treatment of PD. No other medicinal or surgical therapy currently available has been shown to provide antiparkinsonian benefits superior to those achieved with LD.3–5 During the early stages of the disease, immediate release (IR) LD provides a stable response and has an adequate duration of effect. However, as the disease progresses and with continued LD therapy, the duration of effect from each dose progressively decreases and begins to approximate the plasma half-life of the drug. Eventually, patients may fluctuate between periods of “ON” when the subject’s medication is providing benefit with regard to mobility, slowness, stiffness, and periods of “OFF” which is defined as the state when the medication has worn off and is no longer providing benefit. A majority of patients treated with LD will experience motor fluctuations, dyskinesia or other complications within 5 years of treatment. Dyskinesias are involuntary twisting, turning movements which are an effect of medication and occur during the “ON” state. Non-troublesome dyskinesias do not interfere with function or cause meaningful discomfort. Troublesome dyskinesias interfere with function or cause meaningful discomfort. Although several controlled-release (CR) formulations of LD (with CD or benserazide) have been developed, these formulations are associated with erratic absorption and variable LD plasma concentrations.6–8 In addition, the latency to onset of motor improvement is typically 30–90 minutes for the IR formulation and 60–180 minutes with the CR formulation due to the slower absorption.3,9,10 Thus, CR CD–LD is commonly administered with IR CD–LD in patients with fluctuations to improve the control of PD symptoms, particularly for the first dose in the morning.9–12 IPX066 is a multiparticulate extended-release (ER) oral capsule formulation of CD–LD. The CD:LD ratio is 1:4 similar to current CD–LD products. The formulation is designed to provide a rapid initial absorption of LD to achieve therapeutic concentrations of LD and maintain these therapeutic concentrations for an extended duration to assure an early “on” state and sustained efficacy. Pharmacokinetic properties of this formulation and the associated efficacy in patients have been reported previously.13 This report focuses on the development of population pharmacodynamic models for IPX066 and IR CD–LD in patients with advanced idiopathic PD.

The pharmacokinetics and tolerability of single and multiple applications of Nicotine Transdermal Systems (NTS), designed to deliver 14 mg of nicotine per 24 hours, were investigated in 20 healthy adult male smokers. After a single application, mean Cmax and tmax for plasma nicotine were 12.2 ng/mL and 4.4 hours, respectively. Plasma nicotine concentrations rose rapidly and then remained steady between 12 and 24 hours after application. The apparent nicotine half-life (t 1/2) after system removal was 3.2 hours. Steady state was attained by the second day of multiple application, and mean steady-state nicotine Cavg was 25% higher on day 5 compared with the first NTS application. Steady-state plasma cotinine was reached by the fourth day of multiple application and, as with nicotine, Cavg and Cmax increased, tmax decreased, and t 1/2 did not change compared with single application. The mean ratios of cotinine-to-nicotine area under the curve (AUC) values for single and multiple NTS applications were 14.0 and 15.8, respectively. The pharmacokinetics of nicotine and cotinine were linear between single and multiple NTS applications. The nicotine transdermal systems were generally well tolerated.

An open-label, randomized, crossover study determined nicotine pharmacokinetics at steady state of a new Nicotine Transdermal System in 24 healthy adult male smokers. Three doses were each administered for 5 days: 7, 14 and 21 mg nicotine per day. Plasma nicotine concentrations reached steady state by the third day and were sustained throughout the 24-hour application periods. Mean steady-state nicotine and cotinine area under the curve (AUC0-24), maximum plasma concentration (Cmax), minimum plasma concentration (Cmin), average plasma concentration (Cavg), and total urinary cotinine were proportional to the dose of nicotine released in vitro from Nicotine Transdermal System. Time to reach peak concentration (tmax), half-life (t1/2), relative degree of fluctuation (DF) in steady-state plasma nicotine and cotinine concentrations, and renal cotinine clearance were similar for all three dosages, indicating linear pharmacokinetics and no change in nicotine metabolism with increasing dose. Findings from a second study also reflect the linear dose relationship for this Nicotine Transdermal System within the 7 to 21 mg/day dosage range. Bioequivalence based on the confidence interval test was demonstrated for a single application of Nicotine Transdermal System 21 mg/day and the same total dosage achieved by combined administration of Nicotine Transdermal System 7 mg/day plus Nicotine Transdermal System 14 mg/day, although there were small statistical differences. This Nicotine Transdermal System has a well-defined pharmacokinetic profile, with sustained plasma nicotine concentrations, and nicotine pharmacokinetics that are independent of the dose of this Nicotine Transdermal System.

The effect (E) of some drugs may be monitored in vitro using the plasma drug concentration (C) following the in vivo dosing of drug. When using a specific analytical assay, counterclockwise hysteresis in the E vs C relationship can be explained only by the presence of an agonistic metabolite (MA); the extent of hysteresis will depend upon the pharmacokinetics and relative "potency” of C and MA. If a nonspecific assay is used, plots of E vs C may actually relate to E vs total agonist (C + MA), and unusual hysteresis may be observed, e.g., clockwise hysteresis when C is more "potent” than MA. Here, we simulate data for three models of relative C and MA pharmacokinetics. The E vs C and E vs MA data are simulated for both linear and noncompetitive agonist Emax models. When C and MA are equally potent, hysteresis will not be observed in a plot of E vs C + MA. However, when C and MA are of differing "potencies,” hysteresis will be observed (the direction of hysteresis is dependent on the relative potency of C and MA). By appropriately "weighting” a respective agonist (C or MA), hysteresis will "collapse” and the relative potencies of C and MA can be estimated.

The pharmacokinetics of cyclosporine were studied in healthy subjects following administration of cyclosporine both orally (10 mg kg-1) and intravenously (4 mg kg-1) without and with high fat meals. Both blood and plasma samples (separated at 37 degrees C) were analyzed for cyclosporine concentration. Blood and plasma clearances of cyclosporine were calculated to be 0.36 and 0.47 L hr-1 Kg-1, respectively, and volume of distribution at steady state was calculated to be 1.21 L Kg-1, when cyclosporine was administered without a high fat meal. Using plasma analysis, the oral bioavailability of cyclosporine was estimated to be 21 and 79%, when administered without and with a high fat meal, respectively. When cyclosporine was administered intravenously together with a high fat meal, both clearance and volume of distribution increased significantly. Blood and plasma clearances of cyclosporine were 0.44 and 0.70 L hr-1 Kg-1, respectively, when cyclosporine was administered along with a high fat meal. We conclude that food not only enhances the absorption of cyclosporine but also enhances its clearance and volume of distribution. The observed variability in clearance, bioavailability, and volume of distribution values for cyclosporine across various pharmacokinetic studies can be partially accounted by the type of food administered and the sampling matrix used for analysis.

The aim of this study was to compare the pharmacokinetics of immediate-release methylphenidate (MPH) in preschool and school-aged children with attention-deficit/hyperactivity disorder (ADHD).Preschool children 4-5 years (n = 14) and school-aged children 6-8 years (n = 9) with diagnoses of ADHD were titrated to an effective dose of MPH based on parent, teacher, and clinician ratings in a protocol specified by the Preschoolers with ADHD Treatment Study (PATS) and then attended a laboratory school where the single morning dose of immediate release MPH was administered. Blood samples for measurement of MPH concentrations were obtained predose, and at 1, 2, 4, and 6 hours postdose. A nonlinear model was used to derive three pharmacokinetic (PK) values for analysis: Peak plasma concentration (C(max)), half-life (t(1/2)), and clearance (CL).The two groups did not differ in the mean mg dose of MPH (p = 0.33), or in the weight-adjusted mg/kg dose (p = 0.20). Dose-normalized C(max) was significantly higher (p = 0.003), and clearance was significantly slower (p = 0.0002) in preschool than in school-aged children.In this sample, age significantly affected absorption and metabolism of MPH, so that preschool children had greater exposure than school-aged children to the same weight-adjusted dose. These data suggest additional studies should be performed to characterize age-related differences in PK properties of MPH that may inform practitioners about dosing strategies based on the age and size of children being treated.

Background The objective of this study was to compare the pharmacokinetic profile of a novel, once-daily, controlled-release formulation of hydromorphone (OROS® hydromorphone) under fasting conditions with that immediately after a high-fat breakfast in healthy volunteers. The effect of the opioid antagonist naltrexone on fasting hydromorphone pharmacokinetics also was evaluated. Methods In an open-label, three-way, crossover study, 30 healthy volunteers were randomized to receive a single dose of 16 mg OROS® hydromorphone under fasting conditions, 16 mg OROS® hydromorphone under fed conditions, or 16 mg OROS® hydromorphone under fasting conditions with a naltrexone 50-mg block. Plasma samples taken pre-dose and at regular intervals up to 48 hours post-dose were assayed for hydromorphone concentrations. Analysis of variance was performed on log-transformed data; for mean ratios of 0.8 to 1.2 (20%), differences were considered minimal. Bioequivalence was reached if 90% confidence intervals (CI) of treatment mean ratios were between 80% and 125%. Results The mean geometric ratios of the fed and fasting treatment groups for maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-t; AUC0-∞) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-∞ but were slightly higher for Cmax (105.9% and 133.3%, respectively). With naltrexone block, the hydromorphone Cmax increased by 39% and the terminal half-life decreased by 4.5 hours. There was no significant change in Tmax, AUC0-t or AUC0-∞. Conclusion Standard bioavailability measures show minimal effect of food on the bioavailability of hydromorphone from OROS® hydromorphone. Naltrexone co-administration results in a slight increase in the rate of absorption but not the extent of absorption. Trial Registration Clinical Trials.gov NCT00399295

Background The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS® Push-Pull™ osmotic pump technology. Methods In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS® hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS® hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0–∞). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0–∞, and Cmax was used to establish dose linearity and proportionality. Results The study was completed by 31 of 32 subjects. Median Tmax (12.0–16.0 hours) and mean t1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0–48, and AUC0–∞ by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05). Conclusion The pharmacokinetics of OROS® hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses. Trial Registration Clinical Trials.gov NCT00398957

Dapoxetine is a serotonin transporter inhibitor currently in development for the treatment of premature ejaculation. This randomized, 2-sequence, 2-treatment crossover study assessed the single- and multiple-dose pharmacokinetics of dapoxetine following once-daily administration of dapoxetine 30 mg and 60 mg to healthy male volunteers. Dapoxetine was rapidly absorbed following oral administration, with peak plasma concentrations reached approximately 1 hour after dosing; plasma concentrations after single doses of dapoxetine decreased rapidly to approximately 5% of peak concentrations by 24 hours. Elimination was biphasic, with an initial half-life of approximately 1.4 hours and a terminal half-life of approximately 20 hours. Dapoxetine showed time-invariant pharmacokinetics and dose proportionality between doses, and its pharmacokinetics was unaffected by multiple dosing. The pharmacokinetics of dapoxetine metabolites, desmethyldapoxetine and dapoxetine-N-oxide, was similarly unaffected by multiple dosing. There were no serious adverse events; the most commonly reported adverse events were diarrhea, dizziness, and nausea.

Introduction: The fentanyl HCl patient-controlled transdermal system (PCTS) is a noninvasive, needle-free, credit card-sized drug delivery system designed for the on-demand management of acute pain in a medically supervised setting. The objective of these studies was to determine the effect of dosing frequency on the pharmacokinetics of fentanyl delivered by the PCTS. Methods: All three studies were single-centre, open-label, randomised, crossover studies. The fentanyl HCl PCTS was applied to the upper outer arm of all participants. In the first study, participants (n = 30) received three fentanyl HCl PCTS 25μg treatments: two sequential doses hourly for 23.33 hours, six sequential doses every 3 hours for 22 hours, and 72 doses continuously over 12 hours. Participants (n = 31) in the second study received three fentanyl HCl PCTS 40μg treatments: two sequential doses hourly over 23.33 hours, six sequential doses every 3 hours over approximately 10 hours, and 80 doses continuously over 13.33 hours. In the third study, participants (n = 28) received four fentanyl HCl PCTS 40μg treatments: 6, 18, 36 and 80 doses over 1, 3, 6 and 13.33 hours, respectively. Naltrexone was used to block the opioid effects of fentanyl. Pharmacokinetic parameters, including maximum serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum concentration-time curve (AUC) and terminal half-life (t1/2) were determined. Results: In the first study, the dose-normalised AUC (AUCn) values for the 2- and 6-dose sequence treatments were not significantly different (p = 0.937), suggesting that the frequency of dosing has little effect on the amount of fentanyl absorbed; however, the AUCn for the 72-dose treatment was significantly lower than that of the other treatments (p = 0.001), which were of longer duration. The results of the second study paralleled those from the first, suggesting that the bioavailability of fentanyl delivered by the PCTS increases as a function of time and is likely to be independent of dosing frequency. Results from the third study suggested that approximately 40% of the nominal 40μg fentanyl dose is absorbed during the first hour of treatment, with the full nominal dose absorbed after approximately 10 hours. The fentanyl HCl PCTS was well tolerated. Conclusion: The amount of fentanyl absorbed from the PCTS increases as a function of time and is independent of both dosing frequency and total number of doses delivered. The fentanyl HCl PCTS is generally safe and well tolerated.

Aims: To study the dose-ranging population pharmacokinetics of controlled release verapamil in healthy subjects and patients with angina or hypertension. To characterize the pharmacodynamics of controlled-release verapamil in patients with hypertension. Methods: Dose-ranging studies were conducted in healthy volunteers and patients with hypertension and angina. Subjects received doses of 120, 180, 360, or 540 mg racemic verapamil as an osmotic controlled-release formulation. A population pharmacokinetic model involving zero-order release of verapamil into the gastrointestinal tract with first-order absorption and elimination was used to describe the steady-state plasma concentration profile for R- and S-verapamil. A population sigmoid Emax pharmacodynamic model was used to describe the effect of R- and S-verapamil on mean arterial blood pressure. Results:S-verapamil had an approximate 4-fold greater apparent clearance than R-verapamil in both healthy volunteers and patients. The apparent plasma clearance of R- and S-verapamil in healthy volunteers decreased over the dose range of 120–540 mg. A similar dose-dependent decrease in apparent plasma clearance was also noted in patients. None of the patient demographic variables examined (age, total body weight, lean body weight, body mass index, and height) explained the variability in verapamil pharmacokinetics. The pharmacodynamic model describing the relationship between verapamil plasma concentration and mean arterial blood pressure indicated that the S-verapamil had a 3.6-fold lower estimated EC50 compared to R-verapamil. Conclusions: The results from this dose-ranging pharmacokinetic investigation in healthy volunteers and patients are consistent with previous reports in healthy subjects. S-verapamil is cleared more rapidly than R-verapamil and the estimated EC50 for S-verapamil was 3.6-fold lower than for R-verapamil. Estimated EC50 values for R- and S-verapamil decreased with increasing age and decreasing weight. Copyright © 2002 John Wiley & Sons, Ltd.

The effect of food on the pharmacokinetics of 15 mg oxybutynin XL was evaluated in a single-dose, randomized, crossover, open-label study in healthy volunteers. A validated, stereospecific, high-performance liquid chromatography assay was used to simultaneously determine the plasma concentrations of R- and S-oxybutynin and active metabolite R- and S-desethyloxybutynin. The mean AUC and C max values for each of the four analytes in the fed treatment were within ±20% ofthe fasting treatment values. The 90% confidence intervals for the treatment ratios (fed/fasted) for log-transformed C max and AUC inf values for the drug isomers and AUC inf values for the metabolite isomers were all within the 80% to 125% range. Only the ranges for the C max values for Rand S-desethyloxybutynin were slightly wider but were well within the 70% to 143% criteria recommended for C max when comparing effect of food. Lack of effect of food on oxybutynin XL is consistent with the previous observation that the osmotically controlled formulations are nearly insensitive to the gastrointestinal environment, including food. Oxybutynin XL was well tolerated, and the safety results were comparable whether administered alone or with food. In conclusion, oxybutynin XL administration does not require any caution to be exercised regarding food.

The testosterone circadian rhythm has been reported extensively in the literature and has been described by a cosine function. Typically, these data are measured at frequent and regular (e.g., hourly) intervals. However, modeling circadian rhythm with data collected sparsely at irregular intervals and/or data that are not collected at the same time in all individuals has not been reported. The population nonlinear mixed-effects approach can handle such data and also allows covariates to be incorporated into the model. Frequent hourly testosterone concentration data available in the literature for young and elderly healthy volunteers were analyzed first. In the elderly, blunted or completely absent circadian rhythm has been reported, but a full circadian model was significantly better than a model containing one or no circadian component. Therefore, data from both the elderly and young were modeled together, and age was included as a categorical variable (young or elderly). Consistent with literature, the rhythm-adjusted mean testosterone concentrations was lower, and the deviation from the mean, especially to the maximum daily value, was less than half in the elderly (7%) compared to young subjects (16%). The testosterone concentration data measured infrequently and at varying intervals in young normal men and hypogonadal men were evaluated next. Although not measured at regular frequency in each individual, the data were obtained at different clock times for different subjects. Since for population mixed-effects analysis, data from all subjects are pooled, there was enough information to profile the 24-hour circadian cycle. In healthy young subjects, the mean Cnadir, Cpeak, Tnadir, and Tpeak values estimated from the model were 420 ng/dL, 577 ng/dL, 21:42 hours, and 0600 hours, respectively, and were similar to the parameters obtained for the frequently sampled young subjects. In hypogonadal men (testosterone concentrations < 300 ng/dL), the mean testosterone concentrations were much lower than the healthy young or elderly men, and a straight-line model was the best descriptor (i.e., no circadian rhythm was detected). It was also shown that with the application of a transdermal testosterone system, the mean testosterone concentrations in the treated men were within the 95% confidence interval for healthy young men. The results presented here suggest that the advantages of the analysis approach--namely, handling of covariates and handling of sparse, infrequently collected data--can be used in characterizing testosterone circadian rhythm or the lack of it.

Objectives To evaluate the efficacy of several drug delivery patterns of methylphenidate and to determine whether acute tolerance develops to this widely used stimulant medication in the treatment of children with attention deficit hyperactivity disorder. Methods Double-blind trials were conducted in a laboratory school setting in which multiple measures of efficacy were obtained frequently in the morning and afternoon across the school day. In study I, relative efficacy was determined for three dosing patterns of methylphenidate: a standard twice-daily profile, a flat profile, and an ascending profile. In study II, tolerance was assessed by comparison of three-times-a-day regimens in which the time of the middle dose varied. Results In study I, the efficacy of the ascending treatment increased across the day, and in the afternoon it was equal to the efficacy of the twice-daily treatment, indicating that an initial bolus was not required for efficacy. The efficacy of the flat treatment declined across the day, and in the afternoon it was significantly less than in the twice-daily treatment, suggesting that tolerance may be developing. In study II, acute improvements in efficacy were reduced to the second of two closely spaced but not to two widely spaced bolus doses, suggesting that shortly after exposure to high concentrations, efficacy is reduced to given concentrations of methylphenidate. In a concentration–effect model, a tolerance term was needed to account for counterclockwise hysteresis. Conclusions Acute tolerance to methylphenidate appears to exist. This should be considered in the design of an optimal dosing regimen for the treatment of children with attention deficit hyperactivity disorder. Clinical Pharmacology & Therapeutics (1999) 66, 295–305; doi

Background Describing a therapeutic index for a drug is important for evaluating safe and effective dosage regimens. Therapeutic index can be evaluated as the relative position of the dose-efficacy and the dose-side effect curves. Oxybutynin XL (Ditropan XL), a once-daily oral controlled-release formulation for oxybutynin chloride, is being developed. Oxybutynin XL efficacy and side-effect data obtained from two parallel-group, randomized, controlled clinical trials were modeled to evaluate the therapeutic index. Methods A nonlinear mixed-effects model was used to characterize the oxybutynin dose–efficacy and dose–dry mouth relationship. Weekly urge urinary incontinence episodes, the primary efficacy variable, is a discrete variable (counts) with only non-negative integer values and was therefore modeled as a Poisson variable. The probability of dry mouth severity (the most frequently reported side effect), assessed on a categorical four-point scale, was modeled with a proportional odds model. In the modeling process, it was assumed that the time effect was the same for the active and placebo treatments and that the drug effect was additive. Results and Conclusions The urge urinary incontinence episodes declined log-linearly, and no significant difference was observed between the two formulations. However, there was a trend toward higher efficacy with oxybutynin XL than with immediate-release oxybutynin at the same dose in one study. Dose–dry mouth analysis showed that the probability of dry mouth with an increasing dose was significantly lower with oxybutynin XL than with immediate-release oxybutynin in the second study, and a similar trend was observed in the first study. By combining the dose–urge urinary incontinence and dose–dry mouth relationship, a wider therapeutic index was predicted for oxybutynin XL than for immediate-release oxybutynin. Clinical Pharmacology & Therapeutics (1999) 65, 672–684; doi: 10.1016/S0009-9236(99)90089-9

High-fat meals increase the clearance and volume of distribution, but not the mean residence time, of cyclosporine in seven healthy volunteers when either plasma or blood analyses are used. This unexpected finding for a low-extraction ratio drug should not be explainable in terms of increased blood flow. We hypothesize that dietary fat can act as a carrier for cyclosporine and enhance both its volume of distribution and its clearance. We suggest that clearance then occurs following metabolism of lipids due to lipase activity within the hepatocyte, thereby releasing free drug for metabolism.

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate-release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled-release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day, 14 dose, then these samples were analyzed by the gas chromatography method fbr amiptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (C max ) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration-time curve (AUC 0.24 ) for the OROS and IR formulations were 1,265 and 1,393 ng.hr/mL, respectively. The drug-to-metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline-corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance (development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency.