INVESTIGATION OF PHARMACOKINETIC AND PHARMACODYNAMIC INTERACTIONS AFTER COADMINISTRATION OF NEFAZODONE AND HALOPERIDOL

A double-blind, placebo-controlled study using 12 healthy men was desi gned to evaluate pharmacokinetic and pharmacodynamic interactions when nefazodone and haloperidol are coadministered. Two groups of six subj ects each received a 5-mg oral dose of haloperidol or a placebo on stu dy days 1 and 2. Nefazodone, 200 mg, was administered to all 12 subjec ts twice daily (every 12 hours) on study days 3 to 9; on study day 10, only the morning dose of nefazodone was administered. On study days 9 and 10, all subjects also received 5 mg of haloperidol or a placebo a long with the morning dose of nefazodone. Serial blood samples for pha rmacokinetic analysis were collected from each subject over a 12-hour period after the morning dose on study days 1, 2, 9, and 10. Plasma sa mples were assayed for haloperidol, reduced haloperidol, nefazodone, h ydroxynefazodone and m-chlorophenylpiperazine by specific, validated h igh-performance liquid chromatogoraphy methods. Psychomotor performanc e tests to evaluate haloperidol pharmacodynamics were also performed o n days 1, 2, 9, and 10. Reduced haloperidol in the majority of samples was below the limit of quantitation; therefore, the effect of nefazod one on the pharmacokinetics of reduced haloperidol could not be determ ined. The administration of 5 mg of haloperidol to subjects dosed with nefazodone to steady state led to a modest pharmacokinetic interactio n, as indicated by a 36, 13, and 37% increase in mean area under the c urve (AUC(0-12)), highest concentration, and 12-h concentration values for haloperidol, respectively; only the increase in AUC was statistic ally significant. In contrast, the steady-state pharmacokinetics of ne fazodone, hydroxynefazodone, and m-chlorophenylpiperazine were not aff ected by the administration of haloperidol. Although there were signif icant differences observed in some psychomotor performance tests, the effects of nefazodone on the pharmacodynamics of haloperidol could not be consistently demonstrated. The results from this study suggest tha t nefazodone has only modest pharmacokinetic and pharmacodynamic inter actions with haloperidol. Although no specific recommendations can be made, dosage adjustment may be necessary for haloperidol when coadmini stered with nefazodone.