Pharmacokinetic evaluation of co-administration of nefazodone and lithium in healthy subjects

Objectives: To evaluate the possible pharmacokinetic interaction between ne fazodone and lithium. Methods: Twelve healthy volunteers received nefazodone 200 mg b.i.d. for 5 days. A 4-day washout phase followed from day 6 to day 9. From day 10 to da y 20, escalating doses of lithium 250 mg b.i.d. to 500 mg b.i.d. were given ; the daily dose of 1000 mg was obtained on day 13. From day 16 to day 20, nefazodone 200 mg b.i.d. was added to the lithium dosing regimen. Venous bl ood sampling was performed on days 5, 15 and 20 for 0- to 48-h-pharmacokine tic analysis. Nefazodone and its metabolites, hydroxynefazodone, mCPP and t riazoledione were assayed by high-performance liquid chromatography (HPLC). Lithium was assayed by flame photometry. Results: Co-administration of nefazodone did trot modify pharmacokinetic pa rameters of lithium at steady-state. Comparison of the area under the plasm a or serum concentration-versus-time curve calculated from 0-12 h (AUC(0-12 )) Of nefazodone and hydroxynefazodone revealed no significant differences when nefazodone was administered alone or with lithium. The mean maximum pe ak plasma concentration C-max and AUC(0.12) of meta-chlorophenyl-piperazine (mCPP) were significantly reduced by 27% (P < 0.001) and 16% (P < 0.001) w ith the co-administration. The mean C-max and AUC(0-12) of triazoledione we re reduced by 23% (P < 0.005) and 16% (P < 0.01) by the co-administration. Conclusion: Since there were no clinically significant changes in the pharm acokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessa ry when they are co-administered.