Pharmacokinetic Simulations of Aripiprazole 2-Month Ready-To-Use Long-Acting Injectable to Inform Administration in Adult Patients With Schizophrenia or Bipolar-I Disorder

This work was sponsored by Otsuka Pharmaceutical Development & Commercialization Inc. (Princeton, NJ, USA) and H. Lundbeck A/S (Valby, Denmark). Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a novel long-acting injectable formulation of aripiprazole for gluteal administration once every 2 months. A combined population pharmacokinetic model for oral aripiprazole, aripiprazole once-monthly 400 mg (AOM 400), and Ari 2MRTU 960 was developed. Aripiprazole plasma concentration–time profiles were simulated for various Ari 2MRTU treatment initiation and maintenance scenarios. Ari 2MRTU 960 delivered aripiprazole plasma concentrations comparable to AOM 400 in the following initiation scenarios: initiation after a transition from AOM 400; initiation with/without prior stabilization on oral aripiprazole; and initiation on Day 28 after administration of AOM 400 on Day 0 with/without prior stabilization on oral aripiprazole. In scenarios with a delay of 2, 4, 6, and 8 weeks in the maintenance dosing of Ari 2MRTU 960, median trough concentrations of aripiprazole were 191, 144, 110, and 80.1 ng/mL respectively, increasing to 231, 217, 205, and 196 ng/mL at 56 days after the delayed dose was given. In CYP2D6 poor metabolizers, Ari 2MRTU 720 mg showed steady-state aripiprazole concentrations comparable with AOM 300 mg. Compared with Ari 2MRTU 960 without a CYP3A4 or CYP2D6 strong inhibitor, aripiprazole concentrations were similar with Ari 2MRTU 720 plus a CYP3A4 strong inhibitor and higher with Ari 2MRTU 720 with a CYP2D6 strong inhibitor. Simulations showed that aripiprazole plasma concentrations over the 2-month dosing interval with Ari 2MRTU 960 were comparable to those with AOM 400. These data will inform Ari 2MRTU 960 dosing across various clinical scenarios.