Ram P. Kapil

Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration

The effect of dose and gender on the pharmacokinetics (PK) and pharmacodynamics (PD) of zolpidem after administration of a buffered zolpidem sublingual tablet (ZST; Intermezzo®, Purdue Pharma L.P., Stamford, CT, USA) was evaluated in healthy non‐elderly male and female volunteers. Subjects received a single morning dose of ZST (1.0, 1.75, and 3.5 mg) or placebo in a four‐way crossover study. In male and female subjects zolpidem PK were linear, with area under the curve (AUC) proportional to dose, and apparent oral clearance and elimination half‐life independent of dose. However, AUC averaged 40% to 50% higher in females than in males receiving the same dose. The gender effect was incompletely explained by body weight. In females, ZST produced PD changes consistent with benzodiazepine agonist effects, particularly at the 3.5‐mg dose. For several PD variables, PD effects were significantly related to plasma zolpidem concentrations when data were aggregated across subjects. However, there was variability in response among individuals. In males, PD effects of zolpidem seldom differed from placebo regardless of plasma concentration. The findings confirm that zolpidem clearance is lower in females than in males. PD effects of zolpidem from ZST are greater in female subjects, due to a combination of higher plasma concentrations and greater intrinsic sensitivity.

Effect of Ketoconazole on the Pharmacokinetic Profile of Buprenorphine following Administration of a Once-Weekly Buprenorphine Transdermal System

AbstractBackground and Objective: Buprenorphine is extensively metabolized by cytochrome P450 (CYP) 3A4. This study evaluated the effect of ketoconazole, a CYP3A4 inhibitor, on the metabolism of buprenorphine following the administration of a buprenorphine transdermal system 10μg/hour (BTDS 10). Methods: This single-centre study enrolled 20 healthy subjects who had demonstrated ketoconazole-mediated CYP3A4 inhibition via an erythromycin breath test. Subjects were randomized into a placebo-controlled, two-treatment, two-period crossover study. Subjects participated in a 7- to 14-day screening period, two baseline evaluations (day 0 [period 1] and day 16 [period 2]), two 12-day treatment periods (periods 1 and 2) separated by a 4-day washout period, and a study completion visit. Subjects received one BTDS 10 for 7 days per treatment period, administered concomitantly with either ketoconazole 200 mg twice daily or matching placebo. The main outcome measures were the ratios of geometric means for area under the plasma drug concentration versus time curve (AUC) from time zero to time of last measurable concentration (AUClast), AUC from time zero to infinity (AUC∞), and maximum plasma drug concentration (Cmax). Results: The ratio of geometric means (BTDS 10 with ketoconazole/BTDS 10 with placebo) was 99.4 (90% confidence interval [CI] 87.2, 113.3) for AUClast and 97.8 (90% CI 87.7, 109.1) for Cmax. The ratio of geometric means for AUC∞ was 86.7 (90% CI 70.7, 106.2). The plasma concentrations of the metabolites norbuprenorphine and norbuprenorphine-3β-glucuronide were slightly elevated following ketoconazole administration. BTDS 10 with ketoconazole was well tolerated and no apparent safety concerns were noted. Conclusion: The lack of a clinically significant CYP3A4 interaction with ketoconazole following transdermal delivery of buprenorphine is consistent with the parenteral administration of a high clearance drug bypassing exposure to gut wall and hepatic CYP3A4 first-pass effects. Metabolism of buprenorphine during therapy with BTDS is also not expected to be affected by co-administration of other CYP3A4 inhibitors.

Comparison of Pharmacokinetic Profiles of Zolpidem Buffered Sublingual Tablet and Zolpidem Oral Immediate-Release Tablet: Results from a Single-Center, Single-Dose, Randomized, Open-Label Crossover Study in Healthy Adults

BACKGROUND A zolpidem sublingual tablet (ZST) formulation was recently approved by the US Food and Drug Administration to treat middle-of-the-night (MOTN) awakening with difficulty returning to sleep. OBJECTIVE The aim of this study was to compare the zolpidem pharmacokinetic profiles of 3.5-mg ZST and 10-mg immediate-release (IR) oral zolpidem in healthy female and male adults. METHODS This randomized, open-label crossover study compared the pharmacokinetic profile of ZST with that of IR oral zolpidem in healthy adults. RESULTS The study enrolled 19 males and 14 females. After 3.5-mg ZST and 10-mg IR, respectively, mean zolpidem plasma concentrations at 15 minutes (22 vs 17 ng/mL, respectively, in females and 18 vs 10 ng/mL in males) and AUCs from zero to 15 minutes (2.3 vs 0.8 ng · h/mL in females and 1.6 vs 0.5 ng · h/mL in males) were substantially greater for ZST, despite the larger absolute IR dose. After 3.5-mg ZST and 10-mg IR, respectively, clearance was lower in females, even after correcting for body weight (2.63 vs 2.88 mL/min/kg in females and 3.63 vs 3.91 mL/min/kg in males). The lag time prior to the start of first-order absorption was notably shorter for ZST than IR in both males (8 vs 21 minutes) and females (5 vs 22 minutes). Both zolpidem formulations were generally well tolerated by both genders. CONCLUSIONS Systemic exposure of zolpidem was higher in females for both formulations. Plasma levels and AUC were higher, and clearance was lower, in females with both zolpidem formulations. The initial rate of absorption was faster, and initial systemic exposure was greater, with ZST compared with oral IR.

Once-Weekly Transdermal Buprenorphine Application Results in Sustained and Consistent Steady-State Plasma Levels

CONTEXT Transdermal formulations of buprenorphine offer controlled delivery of buprenorphine for sustained analgesic efficacy with reduced adverse events (AEs) compared with the other modes of administration. A buprenorphine transdermal system (BTDS) delivering 5, 10, or 20 mcg/hour for seven days is now marketed in the U.S. as Butrans(®) (Lohmann Therapie-System AG, Andernach Germany), a Schedule III single-entity opioid analgesic indicated for the management of moderate and chronic pain in patients requiring continuous around-the-clock analgesia for an extended period. OBJECTIVES This was a randomized open-label study in healthy subjects to characterize the steady-state buprenorphine pharmacokinetics after the delivery of three consecutive seven-day BTDS applications. METHODS Thirty-seven subjects were randomized to receive three consecutive BTDS 10 mcg/hour (BTDS 10) patches applied to the deltoid or upper back for seven days each. Blood samples for buprenorphine concentration measurements were taken. Safety was assessed using recorded AEs, clinical laboratory test results, vital signs, pulse oximetry, physical examinations, and electrocardiograms. Patch adhesion assessments were taken. RESULTS Analysis of Cmin demonstrated that steady state was reached during the first BTDS 10 application. No significant difference in Cmin was observed across the three applications. Total and peak plasma buprenorphine exposures were similar after each of the seven-day administrations of BTDS. CONCLUSION Three consecutive once-weekly applications of BTDS 10 provided consistent and sustained delivery of buprenorphine. Steady-state plasma concentrations were reached within 48 hours of the first application of BTDS 10. Patch adhesion analysis confirmed the appropriateness of the seven-day application period. Overall, BTDS 10 was safe and well tolerated.

Intranasal Abuse Potential, Pharmacokinetics, and Safety of Once-Daily, Single-Entity, Extended-Release Hydrocodone (HYD) in Recreational Opioid Users

Objectives. A once-daily, extended-release hydrocodone bitartrate tablet with abuse-deterrent properties (Hysingla ER® [HYD]) is available for the treatment of chronic pain in appropriate patients. This study evaluated the intranasal abuse potential and pharmacokinetics of HYD coarse and fine particles vs hydrocodone powder or placebo. Design. Single-center, double-blind, positive- and placebo-controlled, randomized, four-treatment crossover study. Subjects. Healthy adult, nondependent, recreational opioid users with a history of intranasal abuse. Methods. During four treatment periods, subjects (N = 31) received hydrocodone powder 60 mg, HYD coarse particles 60 mg, HYD fine particles 60 mg, or placebo, with five-to-seven-day washouts between treatments. Measures over 36 hours postdose included drug-liking and willingness to take drug again, assessed using visual analog scales (VASs), pupillometry, intranasal irritation, and pharmacokinetics. Results. Insufflation of both HYD coarse and fine particles led to lower “At this Moment” Drug Liking VAS peak values compared with hydrocodone powder, but higher values compared with placebo (P < 0.001 for all comparisons). Similar results were observed for Overall Drug Liking VAS, Take Drug Again VAS, and Subjective Drug Value. Compared with hydrocodone, insufflation of HYD particles led to reduced miosis and increased nasal irritation. Mean hydrocodone Cmax following insufflation of HYD coarse particles, HYD fine particles, and hydrocodone powder was 27.5, 36.5, and 105.8 ng/mL, respectively; median Tmax was ≥2-fold longer with either HYD particle size than hydrocodone powder; and (Cmax/Tmax) was 9.5, 13.4, and 82.0 ng/mL/h, respectively. Safety was consistent with that of opioid agonists. Conclusions. HYD demonstrated reduced intranasal abuse potential compared with hydrocodone powder.

Effects of Paroxetine, a CYP2D6 Inhibitor, on the Pharmacokinetic Properties of Hydrocodone After Coadministration With a Single-entity, Once-daily, Extended-release Hydrocodone Tablet

PURPOSE A single-entity, once-daily, extended-release formulation of hydrocodone bitartrate (HYD) has been developed for the management of moderate to severe chronic pain. Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. CYP3A4 yields norhydrocodone, a major inactive metabolite, whereas CYP2D6 yields hydromorphone, a minor active metabolite. This study examined the influence of the coadministration of paroxetine, a strong selective CYP2D6 inhibitor, on the pharmacokinetic properties of hydrocodone (and hydromorphone) in healthy adults. METHODS In this randomized, double-blind, 2-period, 2-treatment crossover study, 24 healthy subjects received paroxetine 20 mg or placebo once daily for 12 days and an HYD 20-mg tablet on day 10 of each period. FINDINGS Hydrocodone mean Cmax and t½ and median Tmax values were similar with paroxetine or placebo coadministration (16.8 vs 15.9 ng/mL, 8.5 vs 8.4 hours, and 18.0 vs 18.0 hours, respectively), as were mean AUC0-t and AUC0-∞ values (342.9 vs 325.3 ng · h/mL and 346.3 vs 328.5 ng · h/mL). The 90% CIs of the geometric mean ratios of the hydrocodone AUC and Cmax values were fully within the predetermined range of 80% to 125%, suggesting that there was no effect of multiple doses of paroxetine on systemic exposure to hydrocodone. Mean hydromorphone AUC0-t and Cmax values were decreased with paroxetine versus placebo (0.64 vs 3.8 ng · h/mL and 0.06 vs 0.19 ng/mL), whereas Tmax values remained similar (18.0 vs 16.1 hours, respectively). The mean hydromorphone AUC0-∞ value could not be calculated. Both regimens were well tolerated; after HYD administration, the numbers of adverse events were similar between the 2 treatment regimens, and all adverse events were mild. IMPLICATIONS In this study, the coadministration of single-dose HYD with paroxetine at steady state did not alter systemic exposure to hydrocodone, suggesting that HYD can be coadministered with CYP2D6 inhibitors at therapeutic doses, without dosage modification.

Pharmacokinetic Profile and Sustained 24-hour Analgesia of a Once-daily Hydrocodone Bitartrate Extended-release Tablet with Abuse-deterrent Properties.

PURPOSE The purpose of this study was to evaluate the pharmacokinetics (PK) and 24-hour analgesic effectiveness of once-daily, single-entity, extended-release hydrocodone (HYD) with abuse-deterrent properties. METHODS Four studies were included. Three open-label PK studies had the following designs: single-dose, 5-treatment, 4-period, crossover, dose-proportionality study; HYD 120 mg for 5 days (steady-state study 1); 2-treatment, 2-period, multiple-dose crossover study assessing the relative bioavailability of HYD 30 mg and hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours (steady-state study 2). A long-term, open-label study assessed the safety and effectiveness of HYD 20 to 120 mg in patients during a 52-week maintenance period. FINDINGS Thirty-one, 25, and 22 healthy subjects completed the dose-proportionality study, steady-state study 1, and steady-state study 2, respectively, while 410 patients with moderate to severe chronic nonmalignant and non-neuropathic pain completed the long-term effectiveness study. Mean systemic exposure and peak plasma concentration were dose proportional after administration of single doses of HYD 20 to 120 mg. Pharmacokinetic profiles were comparable at day 1 and day 5 after administration of HYD 120 mg once daily. Once-daily HYD 30 mg was associated with lower-fluctuating plasma hydrocodone concentrations compared with immediate-release hydrocodone 7.5 mg/ibuprofen 200 mg administered every 6 hours. In the long-term study, pain control was consistent over the 24-hour dosing interval. IMPLICATIONS Once-daily HYD exhibits linear, dose-proportional PK properties and is associated with a lower variability in plasma hydrocodone concentrations when compared with an immediate-release hydrocodone combination product. Notably, analgesia provided by HYD is sustained during the 24-hour dosing interval. ClinicalTrials.gov identifier: NCT01400139 (Study 4).

Influence of food on pharmacokinetics of zolpidem from fast dissolving sublingual zolpidem tartrate tablets.

Ingesting food can impact the pharmacokinetics of sedative‐hypnotic drugs. A buffered zolpidem sublingual tablet (ZST) recently became available for the treatment of middle‐of‐the‐night awakening. In this randomized, open‐label, single‐site study, the pharmacokinetic profile of ZST was evaluated when administered while fasting and following a standard high‐fat meal (fed state). Healthy adults aged 18–64 years received a single morning dose of 3.5 mg ZST in the fed or fasting state. From 20 min to 3 h post‐dose, zolpidem plasma levels were lower in the fed state compared to the fasting state. After 4 h post‐dose (corresponding to “morning wake time”), higher zolpidem plasma levels were evident in the fed state. Area under the concentration‐time curve (AUC) values for the 0–8 h interval were 160 ng/mL h in the fed state and 203 ng/mL h in the fasting state (P < .001). In the fed versus fasting states, Cmax was 32.0 ng/mL versus 57.3 ng/mL (P < .001), respectively, and Tmax was 3.0 h versus 0.92 h (P < .001), respectively. Together these data suggest that administration of ZST in the fed state is not optimal for maximizing the likelihood of therapeutic benefit and minimizing the probability of residual sedation.