Investigation of Pharmacokinetic and Pharmacodynamic Interactions After Coadministration of Nefazodone and Haloperidol

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Abstract
A double-blind, placebo-controlled study using 12 healthy men was designed to evaluate pharmacokinetic and pharmacodynamic interactions when nefazodone and haloperidol are coadministered. Two groups of six subjects each received a 5-mg oral dose of haloperidol or a placebo on study days 1 and 2. Nefazodone, 200 mg, was administered to all 12 subjects 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 along with the morning dose of nefazodone. Serial blood samples for pharmacokinetic analysis were collected from each subject over a 12-hour period after the morning dose on study days 1, 2, 9, and 10. Plasma samples were assayed for haloperidol, reduced haloperidol, nefazodone, hydroxynefazodone and m-chlorophenylpiperazine by specific, validated high-performance liquid chromatogoraphy methods. Psychomotor performance tests to evaluate haloperidol pharmacodynamics were also performed on days 1, 2, 9, and 10. Reduced haloperidol in the majority of samples was below the limit of quantitation; therefore, the effect of nefazodone on the pharmacokinetics of reduced haloperidol could not be determined. The administration of 5 mg of haloperidol to subjects dosed with nefazodone to steady state led to a modest pharmacokinetic interaction, as indicated by a 36, 13, and 37% increase in mean area under the curve (AUC0-12), highest concentration, and 12-h concentration values for haloperidol, respectively; only the increase in AUC was statistically significant. In contrast, the steady-state pharmacokinetics of nefazodone, hydroxynefazodone, and m-chlorophenylpiperazine were not affected by the administration of haloperidol. Although there were significant 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 that nefazodone has only modest pharmacokinetic and pharmacodynamic interactions with haloperidol. Although no specific recommendations can be made, dosage adjustment may be necessary for haloperidol when coadministered with nefazodone.

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