Quantifying the Exposure of Tapentadol Extended Release in Japanese Patients with Cancer Pain and Bridging Tapentadol Pharmacokinetics Across Populations Using a Modeling Approach.

BACKGROUND AND OBJECTIVES: Tapentadol extended release (ER) is approved for the management of chronic and acute pain in adults. There has been no report of tapentadol ER pharmacokinetics in subjects with cancer pain. This analysis investigated tapentadol ER pharmacokinetics in Japanese patients with cancer pain and bridged it with the pharmacokinetics in Japanese healthy subjects and Caucasian patients with cancer pain. METHODS: Nonlinear mixed-effect pharmacokinetic modeling was conducted based on pooled tapentadol ER concentration data collected in five Phase 1 studies from 138 Japanese and Korean healthy subjects and in two Phase 3 studies from 215 Japanese and Korean subjects with cancer pain. Expected tapentadol exposure in subjects with different characteristics was assessed via simulation. Tapentadol ER exposures in Caucasian populations were compared with those in corresponding Japanese populations. RESULTS: Tapentadol ER pharmacokinetics in Japanese cancer-pain patients were adequately described by a time-invariant, one-compartment disposition model with two input functions and first-order elimination. Weight, age, and albumin were identified as statistically significant covariates, but do not warrant dose adjustment. Comparable pharmacokinetics were shown between Japanese healthy and Caucasian healthy subjects, and between Japanese cancer-pain patients and Caucasian cancer-pain patients. CONCLUSION: The apparent differences in the estimated individual pharmacokinetic parameters in Japanese healthy subjects and Japanese cancer-pain patients taking tapentadol ER were explained by covariates incorporated in a unified pharmacokinetic model. Population modeling was essential in this cross-population bridging analysis.