Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison

Matthew Harlin; Craig Chepke; Frank Larsen; Karimah S Bell Lynum; Sanjeda R Chumki; Heather Fitzgerald; Pedro Such; Jessica Madera-McDonough; Murat Yildirim; Moeen Panni; Stephen R Saklad

doi:10.2147/NDT.S412357

Aripiprazole Plasma Concentrations Delivered from Two 2-Month Long-Acting Injectable Formulations: An Indirect Comparison

Neuropsychiatr Dis Treat. 2023 Jun 8:19:1409-1416. doi: 10.2147/NDT.S412357. eCollection 2023.

Authors

Matthew Harlin^#¹, Craig Chepke^#^{2

3}, Frank Larsen^#⁴, Karimah S Bell Lynum^#⁵, Sanjeda R Chumki^#⁵, Heather Fitzgerald^#⁶, Pedro Such^#⁷, Jessica Madera-McDonough^#⁸, Murat Yildirim^#⁷, Moeen Panni^#⁸, Stephen R Saklad^#⁹

Affiliations

¹ Quantitative Pharmacology, Clinical Pharmacology, Early Phase & Translational Medicine, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA.
² Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
³ Excel Psychiatric Associates, Huntersville, NC, USA.
⁴ Pharmacokinetic and Pharmacodynamic Modelling & Simulation, H. Lundbeck A/S, Valby, Denmark.
⁵ US Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA.
⁶ Medical Affairs, Lundbeck LLC, Deerfield, IL, USA.
⁷ Medical Affairs, H. Lundbeck A/S, Valby, Denmark.
⁸ Global Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA.
⁹ Division of Pharmacotherapy, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA.

^# Contributed equally.

Abstract

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU 960) is a novel long-acting injectable (LAI) formulation of aripiprazole monohydrate for administration once every 2 months, developed for the treatment of schizophrenia or maintenance monotherapy treatment of bipolar I disorder in adults (indication will vary by country). Aripiprazole lauroxil 1064 mg (AL 1064) is an LAI formulation of aripiprazole lauroxil, an aripiprazole prodrug, for administration once every 2 months, indicated for the treatment of schizophrenia in adults. This analysis provides an indirect comparison of aripiprazole plasma concentrations following multiple doses of either formulation. Clinical trial data were used to determine average steady-state aripiprazole plasma concentration (C_avg,ss), maximum aripiprazole plasma concentration (C_max), and other pharmacokinetic parameters of either formulation following four administrations (96 patients received Ari 2MRTU 960; 28 patients received AL 1064). All pharmacokinetic parameters were considered in the context of a minimum aripiprazole therapeutic concentration (C_min) of ≥95 ng/mL. An exposure-response analysis using data from two Phase III trials of aripiprazole once-monthly (an aripiprazole monohydrate LAI, administered monthly), showed that patients with a C_min ≥95 ng/mL are 4.41 times less likely to relapse than patients with a C_min <95 ng/mL. A similar analysis has not been performed for AL 1064. However, consensus guidelines for therapeutic drug monitoring recommend a range of 100-350 ng/mL for aripiprazole. Following four administrations, mean (standard deviation [SD]) C_avg,ss over the 2-month dosing interval was 263 (133) ng/mL for Ari 2MRTU 960 and 140.7 (57.3) ng/mL for AL 1064. Mean (SD) C_max during the fourth dosing interval was 342 (157) ng/mL for Ari 2MRTU 960 and 188.8 (79.8) ng/mL for AL 1064. This indirect comparison showed that, following four administrations, Ari 2MRTU 960 and AL 1064 delivered mean aripiprazole plasma concentrations that remained above the minimum therapeutic concentration of aripiprazole over the 2-month dosing interval.

Keywords: antipsychotic; bipolar I disorder; long-acting injectable; schizophrenia.

Grants and funding

This work was supported by Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA, and H. Lundbeck LLC, Deerfield, IL, USA.