Pooled Post Hoc Analysis of Population Pharmacokinetics of Oxycodone and Acetaminophen Following Multiple Oral Doses of Biphasic Immediate-Release/Extended-Release Oxycodone/Acetaminophen Tablets.

Objective: To examine whether biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325-mg tablets have clinically relevant variability in population pharmacokinetics (PK).

Design: Post hoc analysis of 2 phase 1 randomized, open-label, multiple-dose crossover studies.

Setting: Single contract research organization clinic.

Subjects: Men and women aged 18 to 55 years with a body mass index of 19 to 30 kg/m(2) and body weight ≥ 59 kg.

Methods: Fasted participants (N = 96) received 2 tablets of IR/ER OC/APAP 7.5/325 mg (total dose, 15/650 mg) every 12 hours for 4.5 days. Population PK analysis was performed using nonlinear mixed effects modeling and evaluated 6 population variables.

Results: The average PK estimates for OC were 75 L/hour for clearance (CL/F), 756 L for volume of distribution (V/F), and 0.581 per hour for absorption rate constant (Ka ). Body weight was a statistically significant source of variability in V/F for OC at steady state. Average estimates for APAP were 25 L/hour for CL/F and 119 L for V/F. Sex was identified as a statistically significant source of variability in CL/F with predicted values for APAP of 25 L/hour in men and 21 L/hour in women. Body weight affected variability in V/F, with a predicted value of 193 L in men and 174 L in women for a 72-kg participant at steady state.

Conclusions: Dose adjustments of < 50% are not clinically relevant for IR/ER OC/APAP 7.5/325-mg tablets considering the approved dose of 1 to 2 tablets every 8 to 12 hours; thus, adjustment may be necessary for large deviations from normal body weight but not for sex.