Oxycodone Effect on Pupil Constriction in Recreational Opioid Users: A Pharmacokinetic/Pharmacodynamic Meta-Analysis Approach.

INTRODUCTION: Understanding the effect of oxycodone pharmacokinetics (PK) on µ-opioid receptor binding benefits from an integrated approach to compiling the results of multiple studies. The current pharmacokinetic/pharmacodynamic (PK/PD) model analysis brings together various studies to support the interpretation of newly collected PK/PD data, putting the new results into the perspective of the full concentration-effect curve. METHODS: A two-step modeling approach was applied to characterize the PK of oxycodone and its PK/PD relationship for the pupil diameter as a biomarker for µ-opioid receptor binding in recreational opioid users. First, a model-based meta-analysis (MBMA) was used to quantify the state-of-the-art knowledge from seven published studies, each of which contained part of the data needed for full characterization. Subsequently, the estimated parameters with uncertainty from the MBMA were used as prior information for a model developed on newly collected clinical data after intranasal administration in a clinical abuse potential trial. RESULTS: The inclusion of intravenous data in the MBMA showed that the PK of oxycodone can be described by a two-compartmental model, and allowed for the estimation of absolute bioavailability after intranasal and oral administration. A hysteresis loop was observed when plotting plasma concentrations and pupil constriction, which was approximated using an effect compartment. The totality of literature data enabled the identification of a Hill equation for the drug effect. The model with prior information fitted successfully to the newly collected data, where most parameter estimates had their confidence intervals overlapping with the prior distribution. The new data led to a slightly lower intranasal absorption rate constant, explaining the longer apparent half-life of oxycodone in the newly collected data. The PK/PD model parameters were confirmed by the new data, leading to the following estimates: half maximal inhibitory concentration (IC50) of 26.5 ng/mL, maximum pupil restriction of 66.0% from baseline, and a Hill factor of 1.05. CONCLUSIONS: The new data confirmed the PK profile and the PK/PD relationship identified using the MBMA, resulting in similar parameter estimates except for the intranasal absorption rate constant. The latter was lower than in the MBMA and explained the slightly longer apparent half-life of oxycodone in the newly collected data.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUCtau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the Cmax,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study.

Pharmacokinetic evaluation of tapentadol extended-release tablets in healthy subjects.

OBJECTIVE: To evaluate serum pharmacokinetics of tapentadol administered to healthy subjects as extended-release (ER) tablets. DESIGN: Seven single-dose studies (five randomized, crossover, bioequivalence studies; a study in Japanese men; and a randomized, crossover, effects-of-food study) and one repeated-dose study. SETTING: Clinical research settings in the United States and The Netherlands. PATIENTS OR PARTICIPANTS: Healthy males and females were enrolled into seven studies; one study enrolled only Japanese males. INTERVENTIONS: In the bioequivalence studies, subjects first received one polyethylene oxide- or hypromellose-based tapentadol ER tablet (50, 100, 150, 200, or 250 mg; one dose per study), then (after washout) the other formulation (matching dose). In all other studies, subjects received polyethylene oxide-based tapentadol ER tablets. In the repeated-dose study, subjects received one 250 mg tablet, then (after washout) one 250 mg tablet every 12 hours (five doses). In the food-effect study, subjects received one 250 mg tablet within 30 minutes after a high-fat meal or after 10 hours of fasting. In the study in Japanese men, subjects received one 100 mg tablet. MAIN OUTCOME MEASURES: Maximum tapentadol concentrations (Cmax) were typically observed 5 hours after dosing. Mean terminal half-life values ranged from 4.4 to 5.9 hours. Tapentadol Cmax and AUC values increased proportionally following single ER (polyethylene oxide-based tablets) doses of 50 to 250 mg. Trough tapentadol concentrations increased during repeat dosing until reaching steady-state by the third dose. Serum Cmax and area under the concentration-time curve (AUC) values at steady state were 1.6 and 1.9 times higher relative to single-dose administration. Coadministration of the 250 mg dose with a high-fat meal increased Cmax and AUC values by an average of < 17 percent. CONCLUSIONS: The pharmacokinetics of tapentadol ER are consistent after repeated and single-dose administration. Tapentadol ER may be administered without regard to food intake. No clinically significant differences were observed in the pharmacokinetics of tapentadol between Japanese and Caucasian subjects.

Oral bioavailability of gatifloxacin in healthy volunteers under fasting and fed conditions.

The effect of food on the pharmacokinetics of gatifloxacin given as a single oral dose of 400 mg under fasting and fed conditions was determined in 18 healthy male volunteers in an open, two-way, randomised cross-over study. Concomitant food intake did not significantly alter the peak plasma concentrations (C(max)) or the area under the plasma concentration-time curve (AUC) of gatifloxacin. The mean C(max) levels under fasting and fed conditions were 3.5 and 3.2 mg/l, respectively, after the 400-mg single dose of gatifloxacin. The corresponding mean AUC data were 32.8 mg x h/l (fasted) and 30.5 mg x h/l (fed). Moreover, the rate of absorption was not affected by food intake. The median T(max) value was 2 h in both treatment periods. No clinically relevant adverse effects or changes in clinical laboratory test results, ECGs or physical examinations were observed. The results of this study indicate that gatifloxacin given as a single 400-mg oral dose was well tolerated in the presence or absence of food. Concomitant administration of a continental breakfast with a caloric content of 1,050 kcal had no effect on the bioavailability of gatifloxacin. It is suggested that gatifloxacin can be given without regard to meals.