Pharmacokinetic drug interaction study between overactive bladder drugs mirabegron and tolterodine in Japanese healthy postmenopausal females.
Mirabegron, the first selective β3-adrenoceptor agonist for the treatment of overactive bladder (OAB), inhibits cytochrome P450 isozyme CYP2D6. This study was performed in Japanese healthy postmenopausal female volunteers to assess any pharmacokinetic drug interaction between mirabegron and tolterodine, another OAB drug and a sensitive substrate of CYP2D6. Tolterodine 4 mg was orally administered from Days 1-7 and co-administered with mirabegron 50 mg from Days 8-14. Mirabegron 50 mg increased maximum concentration (Cmax) and area under the concentration-time curve from zero to 24 h after dosing (AUC24h) of tolterodine by 2.06-fold (90% confidence interval [CI] 1.81, 2.34) and 1.86-fold (90% CI 1.60, 2.16), respectively, and increased Cmaxand AUC24hof the metabolite 5-hydroxymethyl tolterodine by 1.36-fold (90% CI 1.26, 1.47) and 1.25-fold (90% CI 1.15, 1.37), respectively. This suggested a weak pharmacokinetic drug interaction between mirabegron and tolterodine. Mean change from baseline of Fridericia's QT correction formula (ΔQTcF) was slightly higher on Day 14 than on Day 7. No subject had QTcF >480 msec or ΔQTcF >60 msec. All the treatment-emergent adverse events were mild. Mirabegron 50 mg was considered to be safe and well tolerated when coadministered with tolterodine 4 mg in healthy postmenopausal female volunteers.
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan. Electronic address: yuki.nomura@astellas.com.
Yuki
Y
Nomura
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Hiromi
H
Iitsuka
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Junko
J
Toyoshima
Data Science, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Kentaro
K
Kuroishi
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Toshifumi
T
Hatta
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Atsunori
A
Kaibara
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Masataka
M
Katashima
Astellas Research Institute of America, 8045 Lamon Avenue, Skokie, IL 60077, United States.
Selina
S
Moy
Clinical Pharmacology, Development, Astellas Pharma Inc., 2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo 103-8411, Japan.
Taiji
T
Sawamoto
D000083:Acetanilides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D058667:Adrenergic beta-3 Receptor Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics; D003408:Cresols / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D013844:Thiazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000068737:Tolterodine Tartrate / Q000009:adverse effects / Q000493:pharmacokinetics*; D064804:Urological Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology
C109909:5-hydroxymethyl tolterodine; D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D001559:Benzhydryl Compounds; D003408:Cresols; D013844:Thiazoles; D064804:Urological Agents; D000068737:Tolterodine Tartrate; C520025:mirabegron
Drug–drug interaction; Japanese; Mirabegron; Overactive bladder; Pharmacokinetics and drug metabolism; Tolterodine