Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects |
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Authors: | Malhotra Bimal Dickins Maurice Alvey Christine Jumadilova Zhanna Li Xiaoxi Duczynski Gregory Gandelman Kuan |
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Affiliation: | 1Pfizer Inc, New York, NY, USA;2Pfizer Global R&D, Sandwich, Kent, UK;3Pfizer Inc, New London, CT, USA |
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Abstract: | AIMSTo assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine.METHODSIn 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,∞)), maximum plasma concentration (Cmax), time to Cmax (tmax), and half-life (t1/2), were assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine.RESULTSConcomitant administration of fesoterodine with fluconazole increased AUC(0,∞) and Cmax 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 tmax or t½. 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.CONCLUSIONFesoterodine 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. |
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Keywords: | drug–drug interactions fesoterodine fluconazole overactive bladder pharmacokinetics |
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