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Pharmacokinetics and Tolerability of Intramuscular, Oral and Intravenous Aripiprazole in Healthy Subjects and in Patients with Schizophrenia

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Abstract

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 1 was an open-label, randomized, three-treatment crossover study in healthy subjects (n= 18) to assess the bioavailability 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 bioavailability 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 [Cmax] 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 Cmax values were similar for the intramuscular and oral formulations. In study 2, the proportionality of the Cmax 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.

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Acknowledgements

This study was sponsored by Bristol-Myers Squibb Company (BMS) [Princeton and Plainsboro, NJ, USA] and Otsuka America Pharmaceutical, Inc. (Rockville, MD, USA). David Boulton and Georgia Kollia are employees of BMS and hold stock in BMS. Bernard Komoroski is an employee of BMS. Suresh Mallikaarjun is an employee of Otsuka Pharmaceutical Development and Commercialization, Inc. Anjali Sharma is currently employed by Allergan, Inc. (Irvine, CA, USA). Lawrence Kovalick is currently employed by Amgen, Inc. (Thousand Oaks, CA, USA) and holds stock in BMS and Amgen Inc. Richard Reeves is currently at RAR Consulting, LLC (Pennington, NJ, USA) and holds stock in BMS.

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Authors and Affiliations

  1. Bristol-Myers Squibb Company, Princeton and Plainsboro, New Jersey, USA

    David W. Boulton, Georgia Kollia, Bernard Komoroski, Anjali Sharma, Lawrence J. Kovalick & Richard A. Reeves

  2. Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, Maryland, USA

    Suresh Mallikaarjun

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  1. David W. Boulton
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  2. Georgia Kollia
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Correspondence to David W. Boulton.

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Boulton, D.W., Kollia, G., Mallikaarjun, S. et al. Pharmacokinetics and Tolerability of Intramuscular, Oral and Intravenous Aripiprazole in Healthy Subjects and in Patients with Schizophrenia. Clin Pharmacokinet 47, 475–485 (2008). https://doi.org/10.2165/00003088-200847070-00004

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