The Bioavailability and Pharmacokinetics of Oral and Depot Intramuscular Haloperidol in Schizophrenic Patients

Abstract

In a four-segment long-term (≥ 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5–35 mg/d for oral haloperidol (mean, 17 mg/d), and 75–500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days. The calculated median IM dose was greater than the actual doses of haloperidol decanoate that had been used. However, clinical results, and not drug plasma concentrations, are the primary determinant of dose level, especially since haloperidol decanoate is given q28d. Thus, the appropriate method for determining the proper dose is to start low and to increase gradually as required by the patient's symptoms.