Single-dose pharmacokinetics of mycophenolic acid following administration of immediate-release mycophenolate mofetil in healthy Beagle dogs.

Mycophenolic acid (MPA) is an immunomodulating agent commonly used in human medicine for the treatment of immune-mediated diseases. There is growing evidence that the immunomodulating properties of mycophenolate mofetil (MMF), a prodrug of MPA, are therapeutically beneficial for the treatment of immune-mediated diseases in dogs. A narrow therapeutic index and high inter-and intra-patient pharmacokinetic (PK) variability complicate the use of MMF. A better characterization of MPA pharmacokinetics is needed to help establish dosing regimens and standardized treatment protocols for canine patients. The purpose of this study was to evaluate the pharmacokinetics of MPA in dogs. MMF oral suspension (10 mg/kg) was administered to five healthy beagle dogs. Serial blood samples were collected from 0 to 18 hours after administration. The simultaneous quantification of MPA, and its metabolites MPA-7-O-glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by liquid chromatography (LC)-mass spectrometry (MS)/MS. MPA peak concentrations were achieved rapidly (median Tmax of 0.5 h). Concentrations fell through 3 hours post-dose and then plateaued around 20% of Cmax. The mean elimination half-life was rapid (5.8 hours) and notable variability was observed in all PK parameters. The PK profiles for the MPAG and AcMPAG metabolites followed a similar pattern as MPA concentration. Future repeat-dose studies will be needed to evaluate steady-state PK parameters and to define therapeutic MPA dose levels.

Pharmacokinetics and Pharmacodynamics of Immediate- and Modified-Release Mycophenolic Acid Preparations in Healthy Beagle Dogs.

Background: Mycophenolic acid (MPA) is a broad-acting immunomodulating agent that may be therapeutically beneficial for the treatment of immune-mediated diseases in canine patients. Objectives: To determine the suppressive effects of MPA on T-cell proliferation, and to assess the feasibility of a canine-specific q24 h modified-release MPA formulation (OKV-1001b). Animals: Fifteen healthy purpose-bred male beagle dogs. Methods: Two nearly identical open-label fifteen-day studies were conducted in which dogs were randomized to receive mycophenolate mofetil (MMF; 10 mg/kg q12h), or two doses of OKV-1001b (270 mg and 180 mg; q24h). Serial pharmacokinetic (PK) and pharmacodynamic (PD) samples were collected on Days 1, 8, and 15. MPA plasma concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), while an ex vivo T-cell proliferation assay assessed PD effects. Dogs were continuously monitored for evidence of side effects and gastrointestinal tolerability. Results: MPA induced inhibition of T-cell proliferation was observed following administration of all MPA preparations in a clear concentration-dependent manner. The PK/PD relationship was maintained across all days and time-points. Data generated herein suggest that MPA plasma concentrations above 600 ng/mL achieve at least 50% inhibition of T-cell proliferation. Conclusions and Clinical Importance: MPA holds therapeutic potential for treating dogs with immune-mediated disease, but clinical trials will be necessary to determine its safety and efficacy in naturally occurring disease. Likewise, q24h oral modified release MPA preparations that maintain MPA plasma concentrations between 600 and 1,000 ng/mL are warranted for further studies in client-owned dogs.

Mycophenolic acid in patients with immune-mediated inflammatory diseases: From humans to dogs.

Mycophenolic acid (MPA), a noncompetitive, selective and reversible inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), is an immunosuppressive agent that has a long history in medicine. Mechanistically, the inhibition of IMPDH leads to the selective and eventual arrest of T- and B-lymphocyte proliferation. Mycophenolate mofetil (MMF), the first MPA-based product to receive marketing approval over two decades ago, was originally indicated for the prophylaxis of organ rejection in human transplant patients. Given its broad immunosuppressive properties and ability to selectively inhibit lymphocyte division and effector functions, the clinical utility of MPA was subsequently explored in a host of autoimmune diseases. Human clinical studies have shown MPA to be safe and effective and support its off-label administration for immune-mediated diseases such as lupus, myasthenia gravis and atopic dermatitis. MMF became generically available in the United States in 2008, and its clinical utility is increasingly being explored as a treatment option for dogs with immune-mediated diseases. This review summarizes the available literature for MPA pharmacokinetics and pharmacodynamics, and the current status of MPA as a treatment for client-owned dogs diagnosed with immune-mediated diseases.

Randomized 5-treatment crossover study to assess the effects of external heat on serum fentanyl concentrations during treatment with transdermal fentanyl systems.

This randomized, open-label, 5-treatment, 5-sequence crossover study was designed to evaluate the effects of a heating pad on serum fentanyl concentrations with reservoir and matrix transdermal fentanyl systems. Subjects were randomized to 1 of 5 treatment sequences, receiving 5 fentanyl treatments (1 per period) for 36 hours: 25 µg/h reservoir without heat, 25 µg/h reservoir with heat, 25 µg/h matrix without heat, 25 µg/h matrix with heat, and a 50 µg/h reservoir without heat. The 25 µg/h systems with heat had a heating pad applied from 0 to 10 and 26 to 36 hours post application. Washout periods between treatments were 5 to 14 days. Naltrexone was given to block the opioid effects of fentanyl. Study results indicate that external heat had a similar effect on both matrix and reservoir systems, with heat applied during the first 10 hours of treatment increasing fentanyl exposure by approximately 61% to 81% at 10 hours (observed serum concentration at 10 hours) and overall exposure (area under the curve from 0 to 10 hours) by approximately 120% to 184%, but had minimal effect from 26 to 36 hours. The increased exposure observed with heat in both 25 µg/h systems, between 0 and 10 hours, was higher than that obtained with the 50 µg/h reservoir system applied without heat.

Evaluation of the abuse potential of extended release hydromorphone versus immediate release hydromorphone.

Immediate release (IR) hydromorphone has experienced significant misuse and abuse. An extended release (ER) hydromorphone formulation has been developed to provide sustained pain relief and may reduce the likelihood for abuse by delaying absorption. In this double-blind, placebo-controlled, randomized, 2-part crossover study, the abuse potential of single oral doses of hydromorphone ER (intact: 16-, 32-, and 64-mg; milled: 8-mg) was compared with 8-mg hydromorphone IR and placebo. After drug administration, subjects with a history of recreational opioid use completed a series of assessments, including subjective effects visual analog scales (eg, drug liking) and Addiction Research Center Inventory With Cole Modification, at several timepoints up to 48 hours postdose. Independent of formulation, maximum at-the-moment drug liking was higher for hydromorphone versus placebo. Maximum drug liking occurred earlier and was higher for 8-mg IR versus 16-mg ER but similar to 32- and 64-mg ER. Most positive effects were lower after 16-mg ER compared with other doses, including 8-mg IR. Bad drug effects were higher for hydromorphone ER, particularly the 64-mg dose. Milled 8-mg ER produced similar subjective effects to 8-mg IR. Comparison of scores after administration of 8-mg IR on 2 separate occasions showed that most assessments exhibited good test-retest reliability, although some scores declined marginally between test and retest. Delayed onset of good drug effects and prominent bad drug effects of hydromorphone ER suggest that, when administered intact, this formulation may have lower abuse potential than hydromorphone IR.

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.

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.

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.

Evaluation of the bioequivalence of two transdermal fentanyl systems following single and repeat applications.

OBJECTIVE: Transdermal delivery of fentanyl has potential benefits over slow-release morphine, being largely preferred by patients owing to the combination of effective pain relief, a good safety profile and easy, pain-free dosing. The new drug-in-adhesive Durogesic D-TRANS fentanyl Matrix Delivery System (DDTDF) has improved pharmaceutical characteristics and patient acceptability compared to the original Durogesic transdermal reservoir system (fentanyl transdermal reservoir), whilst still providing reliable and consistent delivery of fentanyl. The bioequivalence of these two systems was evaluated in two studies. RESEARCH DESIGNS AND METHODS: Eighty healthy volunteers received single (72 h) or multiple (288 h) applications of DDTDF and the transdermal reservoir system (100 microg/h) in two separate randomised, crossover bioequivalence studies. Bioequivalence was assessed by calculating the ratio of least squares means based on log-transformed data following single system application and at steady-state during the fourth application. RESULTS: Both transdermal systems were bioequivalent with respect to all tested pharmacokinetic parameters. Inter-subject variability was comparable between the two systems and was greater than intra-subject variability. Transdermal delivery was well tolerated in both groups. CONCLUSIONS: The pharmacokinetic results demonstrate that DDTDF is bioequivalent to the original fentanyl transdermal reservoir system after single and multiple applications.

Characterisation of the pharmacokinetics of the fentanyl HCl patient-controlled transdermal system (PCTS): effect of current magnitude and multiple-day dosing and comparison with IV fentanyl administration.

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 (p > 0.1) 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. CONCLUSIONS: 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.

The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS).

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 25 microg 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 40 microg 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 40 microg 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 (t(1/2)) 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 40 microg 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.

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.

Effect of the proton pump inhibitor omeprazole on the pharmacokinetics of extended-release formulations of oxybutynin and tolterodine.

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.

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.

New perspectives on the overactive bladder: pharmacokinetics and bioavailability.

In the United States alone, approximately 17 million men and women have symptoms of overactive bladder (OAB). For many years, oxybutynin was the drug of choice for treating OAB. Although it provided effective treatment, multiple daily doses were required, and adverse events, such as dry mouth and constipation, were decided drawbacks. Controlled drug delivery systems seen in commercially available OAB formulations alter the pharmacokinetics of antimuscarinic medications in ways that maintain efficacy and allow once-daily dosing and reduction of adverse events. In the future, OAB medications will not only incorporate new chemical entities, such as the S-enantiomer of oxybutynin, but will also use novel drug delivery technologies, including transdermal patches and bladder implants.

Pharmacokinetics of controlled-release verapamil in healthy volunteers and patients with hypertension or angina.

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 E(max) 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 EC(50) 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 EC(50) for S-verapamil was 3.6-fold lower than for R-verapamil. Estimated EC(50) values for R- and S-verapamil decreased with increasing age and decreasing weight.