Search

Matthew Harlin,1,&ast; Craig Chepke,2,3,&ast; Frank Larsen,4,&ast; Karimah S Bell Lynum,5,&ast; Sanjeda R Chumki,5,&ast; Heather Fitzgerald,6,&ast; Pedro Such,7,&ast; Jessica Madera-McDonough,8,&ast; Murat Yildirim,7,&ast; Moeen Panni,8,&ast; Stephen R Saklad9,&ast; 1Quantitative Pharmacology, Clinical Pharmacology, Early Phase & Translational Medicine, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; 2Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC, USA; 3Excel Psychiatric Associates, Huntersville, NC, USA; 4Pharmacokinetic and Pharmacodynamic Modelling & Simulation, H. Lundbeck A/S, Valby, Denmark; 5US Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; 6Medical Affairs, Lundbeck LLC, Deerfield, IL, USA; 7Medical Affairs, H. Lundbeck A/S, Valby, Denmark; 8Global Medical Affairs, Otsuka Pharmaceutical Development & Commercialization Inc., Princeton, NJ, USA; 9Division of Pharmacotherapy, College of Pharmacy, The University of Texas at Austin, San Antonio, TX, USA&ast;These authors contributed equally to this workCorrespondence: Matthew Harlin, Otsuka Pharmaceutical Development & Commercialization Inc., 508 Carnegie Center Dr, Princeton, NJ, 08540, USA, Tel +1-240-683-3055, Email Matthew.Harlin@otsuka-us.comAbstract: 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 (Cavg,ss), maximum aripiprazole plasma concentration (Cmax), 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 (Cmin) 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 Cmin ≥ 95 ng/mL are 4.41 times less likely to relapse than patients with a Cmin < 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]) Cavg,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) Cmax 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