Dose Proportionality And Pharmacokinetics Of Extended-Release (Oros (R)) Hydromorphone: A Phase 1, Open-Label, Randomized, Crossover Study In Healthy Taiwanese Subjects

Objectives: Osmotic-controlled release oral delivery system (OROS (R)) hydromorphone - an extended-release preparation - is recommended long-term therapy for chronic pain patients. Dose proportionality of OROS hydromorphone has been shown in healthy Caucasian volunteers; however, no studies have been conducted in Asian populations. To determine whether ethnic differences affect the drug's pharmacokinetic (PK) profile, we evaluated the dose proportionality of OROS hydromorphone in healthy Taiwanese adults. Methods: This 12-week, open-label, 4-way crossover, phase 1 study randomly assigned subjects to 1 of 4 treatment sequences - single oral dose OROS hydromorphone: 8 mg, 16 mg, 32 mg, or 64 mg - along with 50 mg naltrexone. Dose proportionality was assessed using a linear mixed-effects model to estimate the slope of the regression line and its 90% CI for C-max, AUC(0-48h), and AUC(last). Descriptive statistics measured plasma hydromorphone concentrations, PK parameters, laboratory analytes, and vital signs. Results: 23 subjects completed the study; a single-dose of OROS hydromorphone increased plasma concentration steadily for 6 hours and sustained it at or near maximum levels for similar to 24 hours. After dose normalization to a 16 mg dose, all studied doses demonstrated dose proportionality for C-max, AUC(last), and AUC(0-48h),as the slopes of the regression lines for C-max, AUC(last), and AUC(0-48h) were close to zero, and the 90% CIs within pre-specified limits. Adverse events were as expected for hydromorphone administered with concomitant naltrexone. Conclusions: Single doses of 8 mg, 16 mg, 32 mg, and 64 mg of OROS hydromorphone were found to be dose proportional for C-max, AUC(last), and AUC(0-48h) and were generally safe and well-tolerated in healthy Taiwanese adults.