PMID- 21545485
OWN - NLM
STAT- MEDLINE
DCOM- 20120102
LR  - 20211020
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 72
IP  - 2
DP  - 2011 Aug
TI  - Effects of the moderate CYP3A4 inhibitor, fluconazole, on the pharmacokinetics of 
      fesoterodine in healthy subjects.
PG  - 263-9
LID - 10.1111/j.1365-2125.2011.04007.x [doi]
AB  - 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.
CI  - (c) 2011 Pfizer Inc.. British Journal of Clinical Pharmacology (c) 2011 The British 
      Pharmacological Society.
FAU - Malhotra, Bimal
AU  - Malhotra B
AD  - Pfizer Inc, New York, NY, USA. bimal.k.malhotra@pfizer.com
FAU - Dickins, Maurice
AU  - Dickins M
FAU - Alvey, Christine
AU  - Alvey C
FAU - Jumadilova, Zhanna
AU  - Jumadilova Z
FAU - Li, Xiaoxi
AU  - Li X
FAU - Duczynski, Gregory
AU  - Duczynski G
FAU - Gandelman, Kuan
AU  - Gandelman K
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Antifungal Agents)
RN  - 0 (Benzhydryl Compounds)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 0 (Muscarinic Antagonists)
RN  - 621G617227 (fesoterodine)
RN  - 8VZV102JFY (Fluconazole)
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - EC 1.14.14.55 (CYP3A4 protein, human)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Analysis of Variance
MH  - Antifungal Agents/*pharmacology
MH  - Area Under Curve
MH  - Benzhydryl Compounds/*pharmacokinetics
MH  - Cross-Over Studies
MH  - Cytochrome P-450 CYP3A/metabolism
MH  - *Cytochrome P-450 CYP3A Inhibitors
MH  - Double-Blind Method
MH  - Drug Interactions
MH  - Female
MH  - Fluconazole/*pharmacology
MH  - Half-Life
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Muscarinic Antagonists/*pharmacokinetics
MH  - Young Adult
PMC - PMC3162656
EDAT- 2011/05/07 06:00
MHDA- 2012/01/03 06:00
PMCR- 2012/08/01
CRDT- 2011/05/07 06:00
PHST- 2011/05/07 06:00 [entrez]
PHST- 2011/05/07 06:00 [pubmed]
PHST- 2012/01/03 06:00 [medline]
PHST- 2012/08/01 00:00 [pmc-release]
AID - 10.1111/j.1365-2125.2011.04007.x [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2011 Aug;72(2):263-9. doi: 10.1111/j.1365-2125.2011.04007.x.