Enrique Bandín-Vilar1,2,3, Francisco Toja-Camba1,2,3, María Vidal-Millares4, María José Durán-Maseda4, Marta Pou Álvarez4, Ana Castro-Balado1,2, Olalla Maroñas5, Almudena Gil-Rodríguez5, Ángel Carracedo5, Irene Zarra-Ferro1,2, Dolors Soy6, Anxo Fernández-Ferreiro1,2, Víctor Mangas-Sanjuan7, Cristina Mondelo-García1,2
1Pharmacy Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain 2FarmaCHUSLab, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain 3Pharmacology, Pharmacy and Pharmaceutical Technology Department, Faculty of Pharmacy, University of Santiago de Compostela (USC), Santiago de Compostela, Spain 4Psychiatry Department, University Clinical Hospital of Santiago de Compostela (SERGAS), Santiago de Compostela, Spain 5Galician Foundation of Genomic Medicine, Foundation of Health Research Institute of Santiago de Compostela (FIDIS), SERGAS, Santiago de Compostela, Spain 6Pharmacy Department, Division of Medicines, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain 7Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, Valencia, Spain
Introduction/Objectives:
Aripiprazole is an atypical antipsychotic widely used in the treatment of schizophrenia, bipolar disorder, and major depressive disorder with psychotic symptoms [1,2]. One of its advantages is the existence of a long-acting injectable formulation. It is mainly metabolized through CYP2D6, giving rise to an active metabolite, dehydroaripiprazole [3]. Due to its interindividual variability, changes in the initially prescribed dosage according to the SmPC are very common to achieve an optimal clinical response with minimal adverse effects. The consensus guidelines establish a therapeutic reference range for minimum concentrations of 100-350 ng/mL for aripiprazole and 150-500 ng/mL for the sum of aripiprazole and dehydroaripiprazole, which is known as the active fraction [4].
The objective of this work is to determine the optimal dosage regimens of LAI aripiprazole across different subgroup of patients, based on a previously developed population pharmacokinetic model.
Methods:
A previously own developed population pharmacokinetic model of aripiprazole and dehydroaripiprazole in patients receiving LAI aripiprazole according to clinical will be used. A 1-compartment model with linear absorption and elimination was proposed to describe both the longitudinal profiles of aripiprazole and dehydroaripriprazole. Weight was a significant covariate of the absorption rate constant (Ka), while the CYP2D6 metabolizing phenotype and the concomitant treatment with strong inhibitors of CYP2D6 were significant covariates of aripiprazole clearance (CLP).
A total of 510 possible scenarios were tested combining the CYP2D6 metabolizing phenotype (poor, intermediate or normal), concomitant treatment or not with strong CYP2D6 inhibitors, the patient’s weight (40, 60, 80, 100, 120, 140, 160 kg), the dose (200, 300, 400, 500, 600 or 700 mg) and the frequency of administration (Q3W, Q4W or Q5W). For each of the possible scenarios, Monte Carlo simulations were performed (n = 1,000) and the probability of reaching the therapeutic reference ranges (PTA) was calculated.
Results:
For poor metabolizers (PM), the 200 mg Q3W regimen was the one with the highest PTA, greater than 95%. When a strong CYP2D6 inhibitor is added, 200 mg Q4W offers the highest PTA, except for patients weighing more than 140 kg, where 200 mg Q5W is recommended.
For intermediate metabolizers (IM), 300 mg Q3W has a PTA close to 100% regardless of weight. If a strong CYP2D6 inhibitor is added, 300 mg Q4W offers the highest PTA values.
For normal metabolizers (NM), the dosing regimen with the highest PTA is 500 mg Q4W. If a strong CYP2D6 inhibitor is added, 300 mg Q4W is the regimen with the highest PTA.
Conclusions:
The Monte Carlo simulations carried out with our own model show that the dosages indicated in the technical data sheet are not those with the greatest probability of reaching the therapeutic reference range in our population. The optimal regimens proposed for our study population range between 200 mg for PM, 300 mg for IM and 500 mg for NM, being 300 mg Q4W in case of NM with concomitant treatment with strong CYP2D6 inhibitors
References:
[1] Stępnicki P, Kondej M, Kaczor AA. Current Concepts and Treatments of Schizophrenia. Mol Basel Switz 2018;23:2087. https://doi.org/10.3390/molecules23082087.
[2] Toja-Camba FJ, Gesto-Antelo N, Maroñas O, Echarri Arrieta E, Zarra-Ferro I, González-Barcia M, et al. Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics. Pharmaceutics 2021;13:935. https://doi.org/10.3390/pharmaceutics13070935.
[3] Tadori Y, Forbes RA, McQuade RD, Kikuchi T. In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors. Eur J Pharmacol 2011;668:355–65. https://doi.org/10.1016/j.ejphar.2011.07.020.
[4] Hiemke C, Bergemann N, Clement HW, Conca A, Deckert J, Domschke K, et al. Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017. Pharmacopsychiatry 2018;51:9–62. https://doi.org/10.1055/s-0043-116492.
Reference: PAGE 32 (2024) Abstr 11217 [www.page-meeting.org/?abstract=11217]
Poster: Clinical Applications