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

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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.

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Acknowledgements

The investigation was conducted at the Clinical Trials Center, Gachon University Gil Medical Center.

Funding

This study was funded by Navipharm Co., Ltd. This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant numbers: HI17C1919 and HI14C2750) and by Gachon University Gil Medical Center (Grant number: FRD2019-11). The journal’s publication fee was funded by the corresponding author (Dongseong Shin).

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Sol Ip Kang is an employee of Navipharm Co., Ltd. The other authors (Chang Hee Kim and Dongseong Shin) have no conflicts of interest to disclose.

Compliance with Ethics Guidelines

This clinical study was conducted in accordance with the recommendations of the Korean Good Clinical Practice and the 1964 Helsinki Declaration and its later amendments (ClinicalTrials.gov registry number: NCT03802526). The Institutional Review Board (IRB) of Gachon University Gil Medical Center approved this protocol and the informed consent form for this study (IRB approval number: GAIRB2019-055). Written informed consent forms were obtained from all participants before enrollment.

Data Availability

The datasets generated during the current study are available from the corresponding author on reasonable request.

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Authors and Affiliations

  1. Department of Urology, Gil Medical Center, Gachon University College of Medicine, Incheon, South Korea

    Chang Hee Kim

  2. Department of Pharmacology, Gachon University College of Medicine, Incheon, South Korea

    Dongseong Shin

  3. Clinical Trials Center, Gachon University Gil Medical Center, Incheon, South Korea

    Dongseong Shin

  4. Clinical Development, Navipharm Co., Ltd., Suwon, South Korea

    Sol Ip Kang

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  1. Chang Hee Kim
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Corresponding author

Correspondence to Dongseong Shin.

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Kim, C.H., Kang, S.I. & Shin, D. Pharmacokinetic Interaction Between Telmisartan and Rosuvastatin/Ezetimibe After Multiple Oral Administration in Healthy Subjects. Adv Ther 38, 1094–1105 (2021). https://doi.org/10.1007/s12325-020-01592-8

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  • DOI: https://doi.org/10.1007/s12325-020-01592-8

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