Carbamazepine-Nefazodone Interaction in Healthy Subjects

Abstract

The pharmacokinetic interaction between nefazodone and carbamazepine was investigated 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 wash-out phase then followed 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 44. A 0- to 48-hour pharmacokinetic analysis was performed on day 38. Nefazodone 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 day 44. Coadministration of nefazodone increased steady-state plasma area under the concentration-time curve (AUC) of carbamazepine from 60.77 (+/-8.44) to 74.98 (+/-12.88) microg x hr/mL (p < 0.001) and decreased the active carbamazepine-10,11-epoxide metabolite AUC concentration from 7.10 (+/-1.16) to 5.71 (+/-0.52) microg x hr/mL (p < 0.005). During the combination, the steady-state AUC of nefazodone decreased from 7,326 (+/-3,768) to 542 (+/-191) ng x hr/mL, and the AUCs of its metabolites (hydroxynefazodone, meta-chlorophenylpiperazine, 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 increased plasma exposure to carbamazepine may warrant monitoring of plasma carbamazepine concentrations with the combination. However, higher doses (>400 mg/day) of carbamazepine could yield more extensive induction, affecting tolerability of the combination. No change in the initial nefazodone dose is necessary, and subsequent dose adjustments should be made on the basis of clinical effects; however, the repercussion of carbamazepine induction of nefazodone metabolism on the antidepressant efficacy has yet to be studied.

Combination therapy with venlafaxine and carbamazepine in depressive patients not responding to venlafaxine: pharmacokinetic and clinical aspects

“…This contrasts with other studies where a comedication with carbamazepine led to a decrease of plasma concentrations of drugs that are CYP3A4 substrates, such as citalopram (Leinonen et al, 1996;Steinacher et al, 2002), mianserin (Eap et al, 1999), nefazodone (Laroudie et al, 2000), sertraline (Khan et al, 2000) and tricyclic antidepressants (Leinonen et al, 1991). The present 'negative' result may be explained by the major pathway of venlafaxine being controlled by CYP2D6, with N-demethylation, which occurs both by CYP2C19 and by CYP3A4, being a minor pathway (Fogelman et al, 1999).…”

N-Dealkylation of Arylpiperazine Derivatives: Disposition and Metabolism of the 1-Aryl-Piperazines Formed

“…In addition, the expression of CYP3A4 can be induced [53] and therefore there is the potential for a number of inducer drugs, herbal supplements and pesticides to increase the clearance with corresponding lower Css levels of these derivatives. This is supported by the observation that in healthy subjects coadministration of carbamazepine (100 to 400 mg/day, depending on the study) substantially reduced exposure to nefazodone and trazodone and their main metabolites (44-94% and 60-76%, respectively) [54][55], again with less effect on ziprasidone AUC (35%) possibly because CYP3A4 mediates only one-third of its biotransformation [22]. Likewise, rifampicin 600 mg/day reduced the mean exposure to buspirone by about 90%, increasing the PmP-to-buspirone ratio about eight-fold in healthy subjects [19].…”

Metabolic drug interactions with new psychotropic agents

“…However, the elimination of lorazepam, a benzodiazepine agent not primarily metabolized by oxidative processes in the liver, was not affected by coadministration of nefazodone [154]. In a recent study concomitant administration of nefazodone with carbamazepine, both substrate and inducer of CYP3A4, resulted in a small increase in plasma carbamazepine levels and a marked decrease in plasma concentrations of nefazodone and its major metabolites [155]. Another in vivo study has shown a modest 35% increase in plasma concentrations of haloperidol, whose metabolism involves CYP3A4 and CYP2D6, when coadministered with nefazodone [156].…”