Pharmacokinetics and tolerability of intramuscular, oral and intravenous aripiprazole in healthy subjects and in patients with schizophrenia

Background and objective: Patients with schizophrenia or bipolar disorder who are experiencing acute behavioural emergencies often require intramuscular injection of antipsychotics for rapid symptom resolution. The efficacy and tolerability of intramuscular aripiprazole injection has been established in agitated inpatients with schizophrenia or bipolar I disorder. The main objective of the two clinical pharmacology studies reported here was to evaluate the pharmacokinetics of aripiprazole after intramuscular dosing in healthy subjects and in patients with schizophrenia, and after intravenous and oral dosing in healthy subjects. Subjects and methods: Study I was an open-label, randomized, three-treatment crossover study in healthy subjects (n = 18) to assess the biclavailability and pharmacokinetics of intramuscular aripiprazole 5 mg and oral aripiprazole 5 mg relative to intravenous aripiprazole 2 mg. Study 2 was an open-label, nonrandomized, escalating-dose study in patients with schizophrenia (n = 32) to evaluate the pharmacokinetics of intramuscular aripiprazole across a range of doses (from 1 mg to 45 mg). Main outcome measures: The noncompartmental pharmacokinetic parameters for plasma concentrations of aripiprazole and its active metabolite dehydro-aripiprazole were determined. Safety and tolerability data are also summarized. Results: In study 1, the geometric mean values for the absolute biclavailability of aripiprazole following oral and intramuscular administration were 0.85 and 0.98, respectively. Intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [C(max)] values at 0.5 hours postdose, respectively). The area under the plasma concentration-time curve (AUC) in the first 2 hours was 90% higher after intramuscular administration than after oral administration. For dehydro-aripiprazole, the AUC over the collection interval values were higher, the times to reach the Cmax values were later and the C(max) values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the C(max) and AUC to doses ranging from 1 mg to 45 mg suggests a linear pharmacokinetic profile for intramuscular aripiprazole. Conclusion: More rapid absorption was observed following intramuscular aripiprazole injection than following oral dosing. These results support the recently reported efficacy of intramuscular aripiprazole for managing agitation in patients with schizophrenia or bipolar I disorder.