Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.
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Malhotra B, Dickins M, Alvey C, Jumadilova Z, Li X, Duczynski G, Gandelman K
Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.
Br J Clin Pharmacol. 2011 Aug;72(2):263-9. doi: 10.1111/j.1365-2125.2011.04007.x.
- PubMed ID
- 21545485 [ View in PubMed]
- Abstract
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Available data suggest that fesoterodine dosage should not exceed 4 mg once daily when taken concomitantly with potent CYP3A4 inhibitors, such as ketoconazole. Currently, no information is available on whether dose adjustment is necessary when fesoterodine is administered with a moderate CYP3A4 inhibitor. WHAT THIS STUDY ADDS: This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor. AIMS: To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine. METHODS: In this open-label, randomized, two-way crossover study, 28 healthy subjects (18-55 years) received single doses of fesoterodine 8 mg alone or with fluconazole 200 mg. PK endpoints, including the area under the plasma concentration-time curve from 0 to infinity (AUC(0,infinity)), maximum plasma concentration (C(max) ), time to C(max) (t(max) ), and half-life (t(1/2) ), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine. RESULTS: Concomitant administration of fesoterodine with fluconazole increased AUC(0,infinity) and C(max) of 5-HMT by approximately 27% and 19%, respectively, with corresponding 90% confidence intervals of (18%, 36%) and (11%, 28%). There was no apparent effect of fluconazole on 5-HMT t(max) or t((1/2)) . Fesoterodine was generally well tolerated regardless of fluconazole co-administration, with no reports of death, serious adverse events (AEs) or severe AEs. Following co-administration of fesoterodine with fluconazole, 13 subjects (48%) experienced a total of 40 AEs; following administration of fesoterodine alone, six subjects (22%) experienced a total of 19 AEs. The majority of AEs were of mild intensity. There were no clinically significant changes in laboratory or physical examination parameters. CONCLUSION: Fesoterodine 8 mg single dose was well tolerated when administered alone or with fluconazole. Based on the observed increase in 5-HMT exposures being within the inherent variability of 5-HMT pharmacokinetics, adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor provided they are not also inhibitors of transporters.
DrugBank Data that Cites this Article
- Drugs
- Drug Enzymes
Drug Enzyme Kind Organism Pharmacological Action Actions Fesoterodine Cytochrome P450 2D6 Protein Humans UnknownSubstrateDetails Fesoterodine Cytochrome P450 3A4 Protein Humans UnknownSubstrateDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareFesoterodineMethimazole The metabolism of Fesoterodine can be decreased when combined with Methimazole. FesoterodineMidostaurin The metabolism of Fesoterodine can be decreased when combined with Midostaurin. FesoterodineRitonavir The metabolism of Fesoterodine can be decreased when combined with Ritonavir. FesoterodineVoriconazole The metabolism of Fesoterodine can be decreased when combined with Voriconazole. FesoterodineEfavirenz The metabolism of Fesoterodine can be decreased when combined with Efavirenz.