Carbamazepine-nefazodone interaction in healthy subjects

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.