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

ObjectiveTo 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). DesignPost hoc analysis of 2 phase 1 randomized, open-label, multiple-dose crossover studies. SettingSingle contract research organization clinic. SubjectsMen and women aged 18 to 55years with a body mass index of 19 to 30kg/m(2) and body weight 59kg. MethodsFasted participants (N=96) received 2 tablets of IR/ER OC/APAP 7.5/325mg (total dose, 15/650mg) every 12hours for 4.5days. Population PK analysis was performed using nonlinear mixed effects modeling and evaluated 6 population variables. ResultsThe average PK estimates for OC were 75L/hour for clearance (CL/F), 756L for volume of distribution (V/F), and 0.581per hour for absorption rate constant (K-a). Body weight was a statistically significant source of variability in V/F for OC at steady state. Average estimates for APAP were 25L/hour for CL/F and 119L for V/F. Sex was identified as a statistically significant source of variability in CL/F with predicted values for APAP of 25L/hour in men and 21L/hour in women. Body weight affected variability in V/F, with a predicted value of 193L in men and 174L in women for a 72-kg participant at steady state. ConclusionsDose 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 12hours; thus, adjustment may be necessary for large deviations from normal body weight but not for sex.