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Population Pharmacokinetics of Olmesartan Following Oral Administration of its Prodrug, Olmesartan Medoxomil

In Healthy Volunteers and Hypertensive Patients

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Abstract

Background

Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype.

Objective

To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. Design: Retrospective analysis of data from 12 phase I–III trials in the US, Europe and Japan.

Participants

Eighty-nine healthy volunteers and 383 hypertensive patients.

Methods

Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function.

Results

The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h−1), elimination rate constant (0.193h−1), rate constant from the central to peripheral compartment (0.061h−1), rate constant from the peripheral to central compartment (0.079h−1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan.

Conclusion

The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 μmol/L [approximately 3 mg/ dL]) could cause a clearance decrease of ≥30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant difference in clearance was found between Westerners and Japanese.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

The authors would like to thank Dr Lewis Sheiner, who sadly passed away in 2004, for his help in reviewing the manuscript.

No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Clinical Pharmacology and Biostatistics Department, Sankyo Company Ltd, Shinagawa-ku, Tokyo, Japan

    Kazutaka Yoshihara & Masafumi Hisaoka

  2. Pharsight Corporation, Mountain View, California, USA

    Yuying Gao & D. Russell Wada

  3. R&D Project Management Department, Sankyo Company Ltd, Shinagawa-ku, Tokyo, Japan

    Hiroshi Shiga

Authors
  1. Kazutaka Yoshihara
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  2. Yuying Gao
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  3. Hiroshi Shiga
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  4. D. Russell Wada
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  5. Masafumi Hisaoka
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Corresponding author

Correspondence to Kazutaka Yoshihara.

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Yoshihara, K., Gao, Y., Shiga, H. et al. Population Pharmacokinetics of Olmesartan Following Oral Administration of its Prodrug, Olmesartan Medoxomil. Clin Pharmacokinet 44, 1329–1342 (2005). https://doi.org/10.2165/00003088-200544120-00011

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  • DOI: https://doi.org/10.2165/00003088-200544120-00011

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