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Role of Cytochrome P450 Isoenzymes 3A and 2D6 in the In Vivo Metabolism of Mirabegron, a β3-Adrenoceptor Agonist

Clinical Drug Investigation volume 33, pages 429–440 (2013)Cite this article

Abstract

Background

Mirabegron is a β3-adrenoceptor agonist for the treatment of overactive bladder. There has been little information published or presented about the involvement of cytochrome P450 (CYP) isoenzymes 3A and 2D6 in the metabolism of mirabegron in humans; in vitro data indicate that oxidative metabolism is primarily mediated by CYP3A with a minor role for CYP2D6.

Objective

To determine to what extent CYP3A and CYP2D6 isoenzymes are involved in mirabegron metabolism.

Methods

Two open-label, randomized, one-sequence crossover drug–drug interaction studies in healthy subjects were conducted to assess the effect of ketoconazole and rifampicin on the pharmacokinetics of mirabegron and two parallel-group studies in healthy subjects with either known confirmed or predicted CYP2D6 phenotype.

Results

Co-administration of multiple dosages of 400 mg/day ketoconazole with a single 100 mg mirabegron oral controlled absorption system (OCAS) dose increased mirabegron maximum concentration (C max) and area under the curve extrapolated to infinity (AUC∞) to 145 % (90 % confidence interval [CI] 123–172 %] and 181 % (90 % CI 163–201 %), respectively. Co-administration of multiple dosages of 600 mg/day rifampicin with a single 100 mg mirabegron OCAS dose decreased mirabegron C max and AUC∞ to 65 % (90 % CI 50–86 %) and 56 % (90 % CI 49–65 %), respectively, without an effect on terminal elimination half-life (t ½). The urinary excretion of mirabegron was increased by ketoconazole and decreased by rifampicin, reflecting the AUC changes, whereas renal clearance was not affected. Ketoconazole decreased mirabegron t ½ from 50.9 to 37.6 h suggesting that volume of distribution as well as first-pass effect decreased. Rifampicin did not affect mirabegron t ½, suggesting that it affects first pass through the intestinal wall or liver. Rifampicin greatly increased the ratio to parent drug of the presumed CYP-mediated mirabegron metabolites M8 and M15 by 777 and 646 %. Steady-state mirabegron pharmacokinetic parameters (50 and 100 mg mirabegron OCAS) were similar in 13 CYP2D6 poor, 40 intermediate, and 99 extensive metabolizers, whereas C max and AUC under the dosing interval τ of 24 h (AUCτ) were 30–47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C max was 14 % and AUC∞ 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t ½. All treatments were well tolerated.

Conclusions

Mirabegron is metabolized by CYP3A and to a minor extent by CYP2D6 in humans. Mirabegron is not considered a sensitive substrate of CYP3A in vivo, as ketoconazole increased mirabegron exposure by less than 2-fold. The effect of CYP2D6 phenotype on mirabegron exposure is small and likely of limited clinical importance.

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Acknowledgments

The authors wish to thank Scott Clark (Gentris) for the genotyping in study 4 and Sandra Boom (Pharma-Plus) for her assistance in the preparation of this manuscript. This study and editorial assistance for the manuscript preparation were funded by Astellas. Jeroen van de Wetering de Rooij is acknowledged for the medical care of the subjects in study 3 and Stewart Harris for the conduct of studies 2 and 4, and critical review of the manuscript. Jennifer Lee, Selina Moy, Donna Kowalski, Michael Roy, and Jim Keirns are employees of Astellas Pharma Global Development Inc. John Meijer, Walter Krauwinkel, and Marcel van Gelderen are employees of Astellas Pharma Europe B.V. Taiji Sawamoto and Shin Takusagawa are employees of Astellas Pharma Inc. Virginie Kerbusch is a consultant for Astellas. Alan Marion has no conflicts of interest to declare.

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Author notes

  1. Alan Marion

    Present address: ICON Development Solutions, Omaha, NE, USA

Affiliations

  1. Astellas Pharma Global Development, Inc., 1 Astellas Way, N2-296, Northbrook, IL, 60062, USA

    Jennifer Lee, Selina Moy, Donna Kowalski, Michael Roy & James Keirns

  2. Astellas Pharma Europe B.V., Leiden, The Netherlands

    John Meijer, Walter Krauwinkel & Marcel van Gelderen

  3. Astellas Pharma Inc., Tokyo, Japan

    Taiji Sawamoto

  4. PharmAspire Consulting, Wijchen, The Netherlands

    Virginie Kerbusch

  5. MDS Pharma Services US Inc., Lincoln, NE, USA

    Alan Marion

  6. Astellas Pharma Inc., Osaka, Japan

    Shin Takusagawa

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Lee, J., Moy, S., Meijer, J. et al. Role of Cytochrome P450 Isoenzymes 3A and 2D6 in the In Vivo Metabolism of Mirabegron, a β3-Adrenoceptor Agonist. Clin Drug Investig 33, 429–440 (2013). https://doi.org/10.1007/s40261-013-0084-y

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Keywords

  • Rifampicin
  • Ketoconazole
  • Mirabegron
  • CYP2D6 Phenotype
  • Oral Control Absorption System