Pharmacokinetic Interaction Between Telmisartan and Rosuvastatin/Ezetimibe After Multiple Oral Administration in Healthy Subjects

Abstract

Introduction: Telmisartan, rosuvastatin and ezetimibe are commonly recommended as combination therapies. However, the pharmacokinetic (PK) interaction among these therapeutic drugs has not been clearly reported. The objective of this study was to investigate possible interactions between telmisartan monotherapy and a fixed-dose combination (FDC) of rosuvastatin/ezetimibe. Methods: A randomized, open-label, multiple oral dose, three-treatment, three-period, six-sequence crossover study was conducted in healthy male volunteers. Monotherapy and cotherapy with telmisartan (80 mg) or a FDC of rosuvastatin and ezetimibe (20/10 mg) were compared after once-daily treatment for 7 days. The PK profiles for telmisartan, rosuvastatin, total ezetimibe (ezetimibe + exetimibe glucuronide) and ezetimibe were evaluated up to 48 h after the last dose. There was a 14-day washout period between each treatment. Results: The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the peak plasma concentration at steady state (Cmax,ss) and area under the plasma concentration-time curve during the dosing interval at steady state (AUCτ,ss) were 1.258 (1.072–1.475) (P = 0.020) and 1.264 (1.167–1.370) (P < 0.001) for telmisartan, 0.796 (0.723–0.878) (P < 0.001) and 0.904 (0.842–0.970) (P = 0.021) for total ezetimibe and 1.237 (1.081–1.416) (P = 0.012) and 0.988 (0.899–1.086) (P = 0.832) for ezetimibe, respectively. With rosuvastatin, the GMR (90% CI) was 2.616 (2.287–2.992) (P < 0.001) for Cmax,ss and 1.265 (1.168–1.369) (P < 0.001) for AUCτ,ss. No serious adverse events or clinically significant results were reported. Conclusions: The coadministration of multiple doses of telmisartan and rosuvastatin/ezetimibe led to a mild increase in systemic exposure with respect to telmisartan and rosuvastatin and a nonsignificant change in exposure to total ezetimibe and ezetimibe, which was not considered clinically significant without safety concerns. Furthermore, for the generalizability of the clinical effects, a large-scaled clinical study might be required in patients with hypertension and dyslipidemia. Clinical Trial Registration: ClinicalTrials.gov registry number: NCT03802526. © 2020, Springer Healthcare Ltd., part of Springer Nature.