title: Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of fesoterodine in healthy subjects.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  This study shows that adjustment of fesoterodine dose is not warranted when co-administered with a moderate CYP3A4 inhibitor.
  
  
  OBJECTIVE
  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,∞)), 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,∞) 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(½) . 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pfizer Inc, New York, NY, USA. bimal.k.malhotra@pfizer.com
authors.forename: Bimal
authors.initials: B
authors.lastname: Malhotra
authors.forename: Maurice
authors.initials: M
authors.lastname: Dickins
authors.forename: Christine
authors.initials: C
authors.lastname: Alvey
authors.forename: Zhanna
authors.initials: Z
authors.lastname: Jumadilova
authors.forename: Xiaoxi
authors.initials: X
authors.lastname: Li
authors.forename: Gregory
authors.initials: G
authors.lastname: Duczynski
authors.forename: Kuan
authors.initials: K
authors.lastname: Gandelman
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D000935:Antifungal Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D015725:Fluconazole / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D001559:Benzhydryl Compounds; D065692:Cytochrome P-450 CYP3A Inhibitors; D018727:Muscarinic Antagonists; C526675:fesoterodine; D015725:Fluconazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human