title: Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia.
abstract: Aripiprazole lauroxil is a linker lipid ester of aripiprazole for extended-release intramuscular (IM) injection. This multicenter, randomized, open-label study evaluated the pharmacokinetics (PK), relative bioavailability, and tolerability of a single IM deltoid or gluteal injection of aripiprazole lauroxil in adult subjects with chronic stable schizophrenia or schizoaffective disorder. Forty-six subjects were randomized 1:1 to aripiprazole lauroxil 441 mg IM in the deltoid or gluteal muscle. Samples were collected through 89 days post-dose to measure levels of aripiprazole lauroxil, N-hydroxymethyl aripiprazole, aripiprazole, and dehydro-aripiprazole. Forty-three (93.5%) subjects completed all study assessments; most were CYP2D6 extensive or immediate metabolizers (96%); two (4%) were poor metabolizers. The PK of aripiprazole following aripiprazole lauroxil was characterized by a steady rise in plasma concentrations (Tmax 44-50 days), a broad peak, and prolonged exposure attributable to the dissolution of aripiprazole lauroxil and formation rate-limited elimination of aripiprazole (t1/2=15.4-19.2 days). Deltoid vs. gluteal administration resulted in slightly higher Cmax aripiprazole concentrations [1.31 (1.02, 1.67); GMR 90% CI]; total exposure (AUCinf) was similar between sites of administration [0.84 (0.57, 1.24)]. N-hydroxymethyl-aripiprazole and dehydro-aripiprazole exposures were 10% and 33-36%, respectively, of aripiprazole exposure following aripiprazole lauroxil. The most common adverse events were injection site pain in 20 subjects (43.5%) and headache in 6 subjects (13.0%) of mild intensity occurring at a similar rate with deltoid and gluteal administration. Exposure ranges with deltoid and gluteal administration overlapped, suggesting that these sites may be used interchangeably. Despite a higher incidence of adverse events, deltoid muscle provides a more accessible injection site and could facilitate patient acceptance.
authors.affiliation: Alkermes, Inc., Waltham, MA, USA. Electronic address: ryan.turncliff@alkermes.com.
authors.forename: Ryan
authors.initials: R
authors.lastname: Turncliff
authors.affiliation: Alkermes, Inc., Waltham, MA, USA.
authors.forename: Marjie
authors.initials: M
authors.lastname: Hard
authors.affiliation: Alkermes, Inc., Waltham, MA, USA.
authors.forename: Yangchun
authors.initials: Y
authors.lastname: Du
authors.affiliation: Alkermes, Inc., Waltham, MA, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Risinger
authors.affiliation: Alkermes, Inc., Waltham, MA, USA.
authors.forename: Elliot W
authors.initials: EW
authors.lastname: Ehrich
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000068180:Aripiprazole; D001682:Biological Availability; D002081:Buttocks; D003692:Delayed-Action Preparations; D057645:Deltoid Muscle / Q000187:drug effects; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D003692:Delayed-Action Preparations; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole
keywords: Aripiprazole; Aripiprazole lauroxil; Atypical antipsychotic; Deltoid; Gluteal; Long-acting injectable; Schizophrenia