Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a beta3-adrenoceptor agonist.

Article Details

Citation

Lee J, Moy S, Meijer J, Krauwinkel W, Sawamoto T, Kerbusch V, Kowalski D, Roy M, Marion A, Takusagawa S, van Gelderen M, Keirns J

Role of cytochrome p450 isoenzymes 3A and 2D6 in the in vivo metabolism of mirabegron, a beta3-adrenoceptor agonist.

Clin Drug Investig. 2013 Jun;33(6):429-40. doi: 10.1007/s40261-013-0084-y.

PubMed ID
23625188 [ View in PubMed
]
Abstract

BACKGROUND: Mirabegron is a beta3-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 (AUCinfinity) 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 AUCinfinity to 65 % (90 % CI 50-86 %) and 56 % (90 % CI 49-65 %), respectively, without an effect on terminal elimination half-life (t((1/2))). 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 (1/2) 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 (1/2), 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 tau of 24 h (AUCtau) were 30-47 % lower in 10 ultrarapid metabolizers. After administration of 160 mg mirabegron immediate release, C(max) was 14 % and AUCinfinity 19 % higher in eight poor metabolizers than in eight extensive metabolizers (phenotyped) with similar t (1/2). 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.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
MirabegronCytochrome P450 2D6ProteinHumans
No
Substrate
Inhibitor
Details
MirabegronCytochrome P450 3A4ProteinHumans
No
Substrate
Details
Drug Interactions
DrugsInteraction
Mirabegron
Ketoconazole
The serum concentration of Mirabegron can be increased when it is combined with Ketoconazole.