Pharmacokinetics and safety of the co-administration of the antiretroviral raltegravir and the lipid-lowering drug ezetimibe in healthy volunteers

Objectives: To assess the pharmacokinetics (PK) of raltegravir and ezetimibe when co-administered to healthy volunteers. Methods: This was a prospective, open-label, crossover study, with subjects randomly assigned to group 1 (raltegravir 400 mg twice daily, raltegravir plus ezetimibe 10 mg once daily, wash-out period, ezetimibe) or group 2 (ezetimibe, raltegravir plus ezetimibe, wash-out period, raltegravir); all phases lasted for 10 days. Steady-state full PK sampling was performed at days 10, 20 and 40. Raltegravir and ezetimibe PK parameters were determined by non-compartmental methods and comparisons in the presence of the potentially interactive drug measured by geometric mean ratio (GMR) and 95% confidence intervals (CIs). Results: Twenty subjects (10 females) completed the study. Raltegravir PK parameters did not change significantly in the presence of ezetimibe: GMRs (95% CI) were 1.16 (0.89-1.51) for AUC(0-12), 1.13 (0.81-1.58) for maximum plasma concentration (C-max) and 1.12 (0.72-1.74) for trough concentration (C-trough). Ezetimibe AUC(0-24) and C-trough were lower in the presence of raltegravir [GMRs (95% CI) were 0.79 (0.68-0.91) for AUC(0-24) and 0.78 (0.60-0.99) for C-trough], while ezetimibe glucuronide C-max was 40% higher (90% CI 1.17-1.66). There was marked inter-individual variability in the PK of the two drugs, especially during co-administration. Conclusions: There were no significant changes in raltegravir PK parameters with or without ezetimibe. However, in the presence of raltegravir, ezetimibe AUC(0-24) and C-trough were significantly lower (> 20%) and ezetimibe glucuronide C-max was higher. Clinical data to assess the importance of the change in ezetimibe concentrations are warranted.