Gayatri Sathyan

Pharmacokinetics of an Oral Once‐a‐Day Controlled‐Release Oxybutynin Formulation Compared with Immediate‐Release Oxybutynin

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 (oxybutynins 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, oxybutynins most frequently reported anticholinergic adverse effect).

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

ABSTRACT 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.

Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss.

Serum testosterone concentrations are frequently in the low-normal range (lowest quartile, <500 ng/dl) in men with AIDS-wasting syndrome (AWS) and in other chronic wasting disorders. The response of patients in this group to androgen treatment has not been determined, however. Eighteen men with AWS (mean +/- standard error [SE]: 87% +/- 1% usual body weight; CD4 count 90 +/- 24) and borderline low serum testosterone concentrations (382 +/- 33 ng/dl) completed a 21-day placebo-controlled inpatient metabolic ward study comparing intramuscular (i.m.) placebo (n = 7) with low-dose (65 mg/week; n = 4) and high-dose (200 mg/week; n = 7) nandrolone decanoate, a testosterone analogue. Nitrogen balance, stable isotope-mass spectrometric measurement of de novo lipogenesis (DNL), resting energy expenditure, and gonadal hormone levels were measured. Both low-dose and high-dose nandrolone resulted in significant nitrogen retention (33-52 g nitrogen/14 days, representing gains of 0.5 to 0.9 kg lean tissue/week) compared with placebo (loss of 11 g nitrogen/week). This was reflected biochemically in a borderline significant reduction of high DNL (p < .06). Serum testosterone and gonadotropins were suppressed whereas resting energy expenditure was unchanged by nandrolone treatment. In 10 study subjects completing a 12-week open-label follow-up phase, body weight increased by 4.9 +/- 1.2 kg, including 3.1 +/- 0.5 kg lean body mass, and treadmill exercise performance also improved. In summary, nandrolone decanoate therapy in the absence of an exercise program in borderline hypogonadal men with AWS caused substantial nitrogen retention compared with placebo, similar in extent to the nitrogen retention previously achieved with recombinant growth hormone. It is reasonable to expand the criteria for androgen treatment in AWS to include at least patients in the lowest quartile of serum testosterone.

Quantitative characterization of therapeutic index: application of mixed-effects modeling to evaluate oxybutynin dose-efficacy and dose-side effect relationships

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.

Fentanyl Delivery from an Electrotransport System: Delivery is a Function of Total Current, Not Duration of Current

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 μA 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 μA for 26 hours plus 4 additional doses at 1,200 μA over 2.5 minutes during hour 1 (group E); or 500 μA for 0.5 hours and 100 μA 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 μA 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.

Pharmacokinetic profile of a 24-hour controlled-release OROS formulation of hydromorphone in the presence of alcohol

ABSTRACT Objective: The purpose of this study was to investigate the pharmacokinetic properties of a novel, once-daily, controlled-release formulation of hydromorphone (OROS* hydromorphone) in the presence of alcohol. * OROS is a registered trade name of ALZA Corporation, Mountain View, CA, USA Research design and methods: In a single-centre, open-label, four-treatment, four-period, four-sequence, crossover study, two groups of 24 healthy subjects (fasted or fed) were randomised to receive four single doses of OROS hydromorphone 16 mg with solutions of either 0%, 4%, 20% or 40% alcohol, and with a naltrexone block. Main outcome measures: Plasma samples taken predose and at regular intervals up to 48 h after dosing were assayed for hydromorphone concentrations; a mixed-effect analysis of variance was done on log-transformed data. Bioequivalence was concluded if 90% confidence intervals of treatment mean ratios were between 80% and 125%. Results: Plasma hydromorphone concentrations were slightly higher after dosing with all alcohol treatments in both the fasted and fed subject groups. Median Tmax values were between 12 and 16 h and ranges were similar for all treatments. Cmax values increased after alcohol compared with no alcohol, with the increase slightly lower in the fed state. The greatest mean increase in Cmax observed was 1.3-fold in the fasted state and 1.1-fold in the fed state. Confidence intervals were within 80–125% for AUC but were slightly higher for Cmax. Conclusions: The pharmacokinetics of once-daily OROS hydromorphone were only minimally affected by alcohol, with no dose dumping of hydromorphone. The results indicate that the controlled-release properties of this formulation are maintained in the presence of alcohol.

Modeling of Circadian Testosterone in Healthy Men and Hypogonadal Men

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.

A comparison of the effects of saliva output of oxybutynin chloride and tolterodine tartrate

BACKGROUND 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. OBJECTIVE 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. METHODS 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. RESULTS 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 (P < 0.01). 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. CONCLUSIONS 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.

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.

AbstractIntroduction: 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 40μg); 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 (25μg) from the PCTS for 23.33 hours, followed by fentanyl (40μg) from the PCTS for 23.33 hours. Intravenous (IV) fentanyl (80 μg/h) was administered intermittently over 24 hours as a reference treatment in Studies I and In study III, participants (n = 28) received fentanyl (40μg) from the PCTS for 20 hours, followed by fentanyl (40μg) 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 (t1/2), 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 170μA resulting in the absorption of 39.5μg 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 40μg. No significant difference existed between the corrected AUC0–5 of the fentanyl HCl PCTS during the single- and multiple-day treatment periods (0.40 and 0.54 μg · 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 40μg. Multiple-day administration does not affect the pharmacokinetics of the fentanyl HCl PCTS 40μg. The system was well tolerated, even after repeated application.

Effects of Application Site and Subject Demographics on the Pharmacokinetics of Fentanyl HCl Patient-Controlled Transdermal System (PCTS)

AbstractIntroduction: 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.