Crossover comparison of IPX066 and a standard levodopa formulation in advanced Parkinson's disease.

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

Pharmacokinetic, pharmacodynamic, and electrocardiographic effects of dapoxetine and moxifloxacin compared with placebo in healthy adult male subjects.

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.

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence and absence of food.

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-infinity) were within 20%. Confidence intervals were within 80% to 125% for AUC0-t and AUC0-infinity 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-infinity. 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.

Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone.

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-infinity). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0-infinity, 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-infinity by dose indicated that the relationship was linear (slope, P < or = 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.

The preparation and human muscarinic receptor profiling of oxybutynin and N-desethyloxybutynin enantiomers.

Oxybutynin (1) is a non-selective muscarinic receptor antagonist that is used clinically for the treatment of urinary incontinence. The major metabolite of oxybutynin in humans is desethyloxybutynin (2). We have prepared the enantiomers of 1 and 2 and evaluated their ability to displace N-CT(3)-scopolamine chloride ((3)H-NMS) binding on human cloned muscarinic m1-5 receptors. Compounds 1 and 2 potently displaced (3)H-NMS binding at m1, m3 and m4 receptors, but were less potent at the m2 and m5 subtypes. However, metabolite 2 was more potent than the parent compound 1 in the binding assay. In general the R enantiomers were more potent than their respective S enantiomers. Therefore, we suggest that the cholinergic side effects associated with 2 may be due to its greater apparent potency with m1 and m3 receptors, especially of its R-enantiomer, when compared with parent drug 1.

Effects of application site and subject demographics on the pharmacokinetics of fentanyl HCl patient-controlled transdermal system (PCTS).

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 25 microg 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 40 microg 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 120 microg 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 microg/L, respectively) and areas under the serum concentration-time curve (AUC24-25; 1.033 and 1.015 microg h/L). However, both Cmax and AUC24-25 were less when the system was applied to the lower inner arm (0.859 microg/L and 0.757 microg x 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.

Population analyses of sustained-release verapamil in patients: effects of sex, race, and smoking.

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.

Effect of antacid on the pharmacokinetics of extended-release formulations of tolterodine and oxybutynin.

BACKGROUND: In general, extended-release (ER) formulations are designed to prolong the duration of efficacy and reduce the adverse effects of a drug. These formulations often contain the entire daily dose in a single tablet. Therefore, failure of the ER mechanism not only diminishes the desired benefits, but may temporarily expose the patient to drug concentrations higher than those released from a conventional tablet. In this study we determined whether pH has an effect on drug release from the ER formulations of oxybutynin (OROS technology) and tolterodine (membrane coated beads) in vitro and in vivo. STUDY DESIGN: In vitro studies were based on standardised dissolution experiments for each drug in media of different pH (artificial gastric fluid at pH 1.2, artificial intestinal fluid at pH 7.5, and water). In the two separate, identically designed in vivo studies, single doses of each drug were administered alone and with an antacid to male and female healthy volunteers aged 18-45 years. The randomised, crossover, open-label in vivo studies employed a validated assay to determine plasma concentrations of tolterodine and its metabolite 5-hydroxymethyl tolterodine (5-HM), or oxybutynin and its metabolite N-desethyloxybutynin. RESULTS: The in vitro study showed similar slow and steady drug release from ER-oxybutynin in each pH medium, with 64-71% released after 12 hours. Drug release from ER-tolterodine was steady and slow in artificial gastric fluid, with 72.5% of drug released after 12 hours. However, drug release was much faster in artificial intestinal fluid and water, where 69.8% and 69.1%, respectively, of the drug was released within 4 hours. These in vitro results were consistent with the findings of the in vivo studies. In vivo, the pharmacokinetic profile (peak plasma concentration [C(max)] and area under the concentration-time curve) of ER-oxybutynin was similar after administration with or without antacid, whereas C(max) values of both tolterodine and 5-HM increased significantly when ER-tolterodine was administered with antacid (p < or = 0.017 vs ER-tolterodine alone). CONCLUSIONS: Changes in pH affected the release of tolterodine from ER-tolterodine, while they had no effect on the release of oxybutynin from the proprietary ER technology used in ER-oxybutynin. The technology employed in ER formulations thus determines sensitivity of drug release to external factors.

Passive absorption of fentanyl from the fentanyl HCl iontophoretic transdermal system.

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

Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form.

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