Food-associated pharmacokinetic differences and variability of a rosuvastatin/ezetimibe fixed-dose combination in replicated bioequivalence studies.

BACKGROUND /

OBJECTIVES

Rosuvastatin/ezetimibe fixed-dose combinations target cholesterol synthesis and intestinal absorption, but pharmacokinetics may differ by analyte, endpoint, and fasted/fed state. This study characterized food-associated pharmacokinetic differences, reference-product within-subject variability, and bioequivalence decision pathways.

METHODS

Data were integrated from two independently conducted, single-center, randomized, open-label, single-dose, two-sequence, four-period, fully replicated crossover bioequivalence trial parts in healthy Chinese adults (ChiCTR2500110429). Free and total ezetimibe and rosuvastatin were evaluated in fasted and fed states. Bioequivalence was assessed separately in each trial part, while exploratory food-associated comparisons used reference-product data averaged across replicated periods within participants.

RESULTS

Food-associated patterns differed by analyte and endpoint. Fed-to-fasted geometric mean ratios (GMRs) for free ezetimibe were 258.8% for maximum plasma concentration (Cmax), 125.9% for area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t), and 127.1% for area under the concentration-time curve from time zero to infinity (AUC0-∞). For total ezetimibe, the Cmax GMR was 152.4%, whereas AUC shifts were smaller than the free ezetimibe. Rosuvastatin GMRs were 47.7%, 59.2%, and 60.8% for Cmax, AUC0-t, and AUC0-∞, respectively. Within-subject coefficients of variation (CVW%) differed by analyte, endpoint, and state. All primary endpoints met average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) criteria in both states. No serious or grade ≥ 2 adverse events or adverse-event-related withdrawals occurred.

CONCLUSIONS

Food-associated pharmacokinetic differences were analyte- and endpoint-dependent, whereas formal bioequivalence was demonstrated in both states. These findings support separate interpretation of food-associated pharmacokinetics, reference-product variability, and bioequivalence in multi-analyte fixed-dose combination evaluation.