The pharmacokinetic interaction between nefazodone and carbamazepine was in
vestigated in 12 healthy male volunteers. Subjects received nefazodone 200
mg twice daily for 5 days, and blood sample collection was performed on day
5 for 0- to 48-hour pharmacokinetic analysis. A 4-day washout phase then f
ollowed from days 6 to 9, Carbamazepine 200 mg was administered once daily
from days 10 to 12, and then 200 mg was given twice daily from days 13 to 4
4, A 0- to 48-hour pharmacokinetic analysis was performed on day 38, Nefazo
done 200 mg twice daily was added to the dosing regimen from days 40 to 44,
and a subsequent 0- to 48-hour pharmacokinetic analysis was performed on d
ay 44. Coadministration of nefazodone increased steady-state plasma area un
der the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44
) to 74.98 (+/-12.88) mu g.hr/mL (p < 0.001) and decreased the active carba
mazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to
5.71 (+/-0.52) mu g.hr/mL (p < 0.005). During the combination, the steady-s
tate AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng.h
r/ml, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenyl
piperazine, and triazoledione) decreased significantly as well (p < 0.001),
Coadministration of nefazodone 200 mg twice daily and carbamazepine 200 mg
twice daily was found to be safe and well tolerated; however, the increase
d plasma exposure to carbamazepine may warrant monitoring of plasma carbama
zepine concentrations with the combination. However, higher doses (>400 mg/
day) of carbamazepine could yield more extensive induction, affecting toler
ability of the combination. No change in the initial nefazodone dose is nec
essary, and subsequent dose adjustments should be made on the basis of clin
ical effects; however, the repercussion of carbamazepine induction of nefaz
odone metabolism on the antidepressant efficacy has yet to be studied.