The single dose and steady-state pharmacokinetics of buspirone and its metabolite 1-pyrimidinyl piperazine (1-PP) have been evaluated in normal volunteers and patients with renal or hepatic impairment, using a parallel group design, with assignment of patients to study group on the basis of the degree of renal (mild, moderate, severe) or hepatic (compensated or decompensated) impairment. Each healthy volunteer or patient received a single dose of 10 mg buspirone on Day 1 of the study, and starting 36 h after the first dose, healthy volunteers and patients received 10 mg doses of buspirone every 12 hours for 9 days. On the morning of Day 10 they received the last dose. Serial blood samples were collected on Days 1, 5 and 10 and plasma was analysed for buspirone and 1-PP. The plasma concentrations of buspirone and 1-PP were highly variable regardless of the renal or hepatic function. The peak concentrations (Cmax) and area under the curves (AUC) of buspirone and 1-PP on Days D5 and 10 were higher than on Day D1. The trough levels (Cmin) and AUCs (D5 and 10) of buspirone and 1-PP indicated, that, regardless of renal or hepatic function, steady state was reached after 3 to 5 days of dosing. At steady-state, patients with renal or hepatic impairment had significantly higher Cmax and AUC values of buspirone than in normal volunteers. However, the intensity and frequency of adverse experiences in patients with renal or hepatic impairment were not significantly different from those observed in normal volunteers.(ABSTRACT TRUNCATED AT 250 WORDS)

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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.

Since there were no clinically significant changes in the pharmacokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessary when they are co-administered.