Alternative Pharmacokinetic Metrics in Single-Dose Studies to Ensure Bioequivalence of Prolonged-Release Products at Steady State-A Case Study.

(1) Background: this article investigates which PK metrics in a single-dose study (concentration at the end of posology interval, C τ , partial areas under the curve, pAUCs, or half-value duration, HVD) are more sensitive and less variable for predicting the failure of a prolonged-release product at steady-state that was the bioequivalent for C max , AUC 0-t and AUC 0-inf , in the single-dose study; (2) Methods: a cross-over study was performed in 36 subjects receiving desvenlafaxine 100 mg prolonged-release tablets. Conventional (C max , AUC 0-t and AUC 0-inf ) and additional (C τ , pAUCs and HVD) PK metrics were considered after single-dose conditions. Predicted PK metrics at steady state (AUC 0-τ , C max,ss , and C τ,ss ) were derived using a population PK model approach; (3) Results: the existing differences in the shape of the concentration-time curves precluded to show equivalence for C τ,ss in the simulated study at steady state. This failure to show equivalence at steady state was predicted by C τ , pAUCs and HVD in the single-dose study. C τ was the most sensitive metric for detecting the different shape, with a lower intra-subject variability than HVD; (4) Conclusions: conventional PK metrics for single-dose studies (C max , AUC 0-t and AUC 0-inf ) are not enough to guarantee bioequivalence at steady state for prolonged-release products.