DOI 10.5414/CP201782

Int. Journal of Clinical Pharmacology and Therapeutics, Volume 50 - November (838 - 850)

Single dose pharmacokinetics and absolute bioavailability of mirabegron, a β3-adrenoceptor agonist for treatment of overactive bladder

Charlotte Eltink1, Jennifer Lee2, Marloes Schaddelee1, Wenhui Zhang2, Virginie Kerbusch6, John Meijer1, Sjoerd van Marle3, Nicole Grunenberg4*, Donna Kowalski2, Ted Drogendijk1, Selina Moy2, Hiromi Iitsuka5, Marcel van Gelderen1, Hiroshi Matsushima5, Taiji Sawamoto5
1 Astellas Pharma Europe BV, Leiderdorp, The Netherlands, 2 Astellas Pharma Global Development Inc., Northbrook, IL, USA, 3 PRA International, Zuidlaren, The Netherlands, 4 Charles River Clinical Services Northwest Inc. (now: Comprehensive Clinical Development), Tacoma, WA, USA, 5 Astellas Pharma Inc., Hasune, Tokyo, Japan, 6 PharmAspire Consulting, Wijchen, The Netherlands

Abstract

Background and objectives: Mirabegron is a potent and selective β3-adrenoceptor agonist in development for treatment of overactive bladder. Methods: Mirabegron pharmacokinetics after single intravenous (i.v.) and oral doses, absolute bioavailability (F), dose proportionality, sex differences and tolerability were assessed in 2 single-dose, open-label, randomized, parallel-group, cross-over studies in healthy men (exploratory Study 1, n = 12) and men and women (Study 2, n = 91). Results: After oral dosing (25 – 150 mg), peak plasma concentrations were attained after ~ 4 h. Mean half-life was around 40 h for both routes of administration. Volume of distribution at steady state was 1,670 l and total clearance was around 57 l/h for i.v. dosing. Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 – 50 mg), but exposure increased more than proportionally after oral dosing due to increased F (29% for 25 mg to 45% at 150 mg). About 20% of the (absorbed) dose was excreted unchanged into urine. Area under the curve (AUC) was 27% and 64% higher in females than males after i.v. and oral dosing respectively; differences were mostly attributed to body weight, and for oral dosing, also to F. Conclusions: Mirabegron pharmacokinetics were linear after i.v. dosing (7.5 – 50 mg), but increased more than proportionally after oral dosing (25 – 150 mg) as a result of increased F. Sex differences in exposure could be explained by body weight and for oral dosing, also by F. Mirabegron was in general well tolerated up to the highest doses studied, 50 mg i.v. and 150 mg oral.

Author Details

Authors

  • Charlotte Eltink1
  • Jennifer Lee2
  • Marloes Schaddelee1
  • Wenhui Zhang2
  • Virginie Kerbusch6
  • John Meijer1
  • Sjoerd van Marle3
  • Nicole Grunenberg4*
  • Donna Kowalski2
  • Ted Drogendijk1
  • Selina Moy2
  • Hiromi Iitsuka5
  • Marcel van Gelderen1
  • Hiroshi Matsushima5
  • Taiji Sawamoto5

Departments

  • 1 Astellas Pharma Europe BV, Leiderdorp, The Netherlands,
  • 2 Astellas Pharma Global Development Inc., Northbrook, IL, USA,
  • 3 PRA International, Zuidlaren, The Netherlands,
  • 4 Charles River Clinical Services Northwest Inc. (now: Comprehensive Clinical Development), Tacoma, WA, USA,
  • 5 Astellas Pharma Inc., Hasune, Tokyo, Japan,
  • 6 PharmAspire Consulting, Wijchen, The Netherlands

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