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Cited by 17Schizophrenia research and treatmentPharmaceutical studies and practicesPharmacogenetics and Drug Metabolism

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Pharmacokinetic Evaluation of a 1-Day Treatment Initiation Option for Starting Long-Acting Aripiprazole Lauroxil for Schizophrenia

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Hard, Marjie L., Wehr, Angela Y., Du, Yangchun, Weiden, Peter J., Walling, David, von Moltke, Lisa·2018·Journal of Clinical Psychopharmacology
DOI 10.1097/jcp.0000000000000921PMC PMC6133194
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Abstract

Background: Aripiprazole lauroxil (AL), a long-acting injectable antipsychotic for the treatment of schizophrenia, requires 21 days of oral aripiprazole supplementation upon initiation. We report findings from a phase 1 study investigating a nanocrystalline milled dispersion of AL (AL NCD) as a potential 1-day initiation regimen. The 1-day initiation regimen is designed to enable rapid achievement of plasma aripiprazole concentrations that are comparable with the 21-day oral initiation regimen. Here, a 6-month pharmacokinetic study compared 2 different initiation regimens for starting AL. Methods: Patients were randomized 1:1:1:1 to receive 1 of 4 treatments consisting of the 1-day (single AL NCD injection + one 30-mg dose of oral aripiprazole on day 1 only) or the 21-day (15-mg daily dose of oral aripiprazole for 21 days) initiation regimen, each combined with a starting AL dose of either 441 mg or 882 mg. Results: In total, 133/161 patients completed the study. The pharmacokinetic profile of the 1-day initiation regimen was comparable to the 21-day initiation regimen; both achieved aripiprazole concentrations in the therapeutic range within 4 days and remained in a comparable concentration range during treatment initiation. Common adverse events (≥5.0%) were injection-site pain, headache, increased weight, insomnia, dyspepsia, and anxiety. Nine akathisia events occurred (4 events in 4 patients and 5 events in 2 patients in the 1-day and 21-day initiation regimen groups, respectively). Conclusions: The 1-day initiation regimen resulted in plasma aripiprazole concentrations consistent with the 21-day initiation regimen. Therefore, a single dose of AL NCD with a single 30-mg oral dose of aripiprazole provides an alternative initiation regimen for starting AL.

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FIGURE 1 Study design. Patients were admitted to an inpatient facility on day −1 and were discharged after assessments on day 15. After discharge, patients received outpatient follow-up assessments until day 141. *Patients naive to aripiprazole were administered 5-mg test doses of oral aripiprazole on day −30 and day −29. †Patients in the 1-day initiation groups were treated as follows: ALNCD intramuscular (gluteal) plus 30-mg oral aripiprazole plus either intramuscular AL 441 mg (deltoid) or AL 882 mg (contralateral gluteal) on day 1 followed by 20 days of oral placebo. ‡Patients in the 21-day initiation groups were treated as follows: placebo injection (gluteal) plus 15-mg oral aripiprazole plus either intramuscular AL 441 mg (deltoid) or AL 882 mg (contralateral gluteal) on day 1 followed by 20 days of 15-mg oral aripiprazole.
FIGURE 1 Study design. Patients were admitted to an inpatient facility on day −1 and were discharged after assessments on day 15. After discharge, patients received outpatient follow-up assessments until day 141. *Patients naive to aripiprazole were administered 5-mg test doses of oral aripiprazole on day −30 and day −29. †Patients in the 1-day initiation groups were treated as follows: ALNCD intramuscular (gluteal) plus 30-mg oral aripiprazole plus either intramuscular AL 441 mg (deltoid) or AL 882 mg (contralateral gluteal) on day 1 followed by 20 days of oral placebo. ‡Patients in the 21-day initiation groups were treated as follows: placebo injection (gluteal) plus 15-mg oral aripiprazole plus either intramuscular AL 441 mg (deltoid) or AL 882 mg (contralateral gluteal) on day 1 followed by 20 days of 15-mg oral aripiprazole.CC BY-NC-ND · PubMed Central
FIGURE 2 Mean (+SD) aripiprazole concentrations over time (28 days) after treatment initiation with oral aripiprazole (15 mg over 21 days) or ALNCD plus a single dose of oral aripiprazole (30 mg). Data displayed in Figure 2 represents the first 28 days displayed in Figure 3.
FIGURE 2 Mean (+SD) aripiprazole concentrations over time (28 days) after treatment initiation with oral aripiprazole (15 mg over 21 days) or ALNCD plus a single dose of oral aripiprazole (30 mg). Data displayed in Figure 2 represents the first 28 days displayed in Figure 3.CC BY-NC-ND · PubMed Central
FIGURE 3 Mean (+SD) aripiprazole concentrations over time (140 days) for treatment initiation with ALNCD plus a single dose of oral aripiprazole (30 mg) or oral aripiprazole (15 mg over 21 days).
FIGURE 3 Mean (+SD) aripiprazole concentrations over time (140 days) for treatment initiation with ALNCD plus a single dose of oral aripiprazole (30 mg) or oral aripiprazole (15 mg over 21 days).CC BY-NC-ND · PubMed Central
FIGURE 4 Box plot of AUC0–28 for aripiprazole, by starting AL dose/initiation regimen. The boxes represent the 25th and 75th percentiles of aripiprazole concentration, the line within each box marks the median, the asterisk indicates the mean, and the whiskers indicate the 10th and 90th percentiles. The squares represent individual observations beyond the 10th and 90th percentiles. *AUC0–28 values could not be estimated for all patients because some patients discontinued the study before day 28.
FIGURE 4 Box plot of AUC0–28 for aripiprazole, by starting AL dose/initiation regimen. The boxes represent the 25th and 75th percentiles of aripiprazole concentration, the line within each box marks the median, the asterisk indicates the mean, and the whiskers indicate the 10th and 90th percentiles. The squares represent individual observations beyond the 10th and 90th percentiles. *AUC0–28 values could not be estimated for all patients because some patients discontinued the study before day 28.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Hard, M. L., Wehr, A. Y., Du, Y., Weiden, P. J., Walling, D., & von Moltke, L.
Affiliations
  • Alkermes (United States) (US)
  • Collaborative Neuroscience Network (US)
  • Alkermes, Inc, Waltham, MA; and
Corresponding author
  • Hard, Marjie L.
  • Wehr, Angela Y.
  • Du, Yangchun
  • Weiden, Peter J.
ORCID
Venue
Journal of Clinical Psychopharmacology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2018-10
Volume
38
Issue
5
Pages
435-441
ISSN
  • 0271-0749 (ISSN-L)
  • 1533-712X
DOI
10.1097/jcp.0000000000000921
PMC
PMC6133194
OpenAlex
W2883349192
Cited by
17
References
21
Citations by year
2025: 3 · 2024: 2 · 2023: 2 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 1
FWCI
1.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Clinical Psychopharmacology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmaceutical studies and practices
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords
aripiprazole lauroxil, long-acting injectable antipsychotics, schizophrenia, pharmacokinetics, akathisia, injection site pain
MeSH terms
Aripiprazole, Administration, Oral, Adult, Delayed-Action Preparations, Double-Blind Method, Drug Administration Schedule, Female, Humans, Injections, Intramuscular, Male, Middle Aged, Schizophrenia, Antipsychotic Agents, Treatment Outcome

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