Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.

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.

This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor.
To assess the effects of fluconazole, a moderate CYP3A4 inhibitor, on the pharmacokinetics (PK) and safety/tolerability of fesoterodine.

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,∞)), maximum plasma concentration (Cmax), time to Cmax (tmax), and half-life (t1/2) re assessed for 5-hydroxymethyl tolterodine (5-HMT), the active moiety of fesoterodine.

Concomitant 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 t1/2 . 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.

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.

Bimal Malhotra, Maurice Dickins, Christine Alvey, Zhanna Jumadilova, Xiaoxi Li, Gregory Duczynski, Kuan Gandelman
August 1, 2011
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