Understanding inter-individual variability in pharmacokinetics/pharmacodynamics of aripiprazole in children with tic disorders: Individualized administration based on physiological development and CYP2D6 genotypes

Abstract

Objective: This study aims to develop a combined population pharmacokinetic (PPK) model for aripiprazole (ARI) and its main active metabolite dehydroaripiprazole (DARI) in pediatric patients with tic disorders (TD), to investigate the inter-individual variability caused by physiological and genetic factors in pharmacokinetics of ARI and optimize the dosing regimens for pediatric patients.Methods: A prospective PPK research was performed in Chinese children with TD. Totally 84 patients aged 4.83–17.33 years were obtained for the pharmacokinetic analysis. 27 CYP2D6 and ABCB1 gene alleles were detected. Moreover, the clinical efficacy was evaluated according to reduction rate of Yale Global Tic Severity Scale (YGTSS) score at the 12th week comparing with the baseline. Monte Carlo simulations were used to evaluate and optimize dosing regimens.Results: The PPK model was established to predict the concentrations of ARI and DARI. Body weight and CYP2D6 genotype were the significant covariates affecting the clearance of ARI. The DARI/ARI metabolic ratios (MRs) of AUC24h, Cmin and Cmax at the steady state of results were ultra-rapid metabolizers (UMs) > normal metabolizers (NMs) > intermediated metabolizers (IMs). MRs could be used to distinguish UMs or IMs from other patients. The best predictor of clinical efficacy for TD was the trough concentration of ARI and the cut-off point was 101.636 ng/ml.Conclusion: The pharmacokinetics of ARI and DARI in pediatric TD were significantly influenced by body weight and CYP2D6 genotype. Individualized dosing regimens were recommended for pediatric patients with TD to ensure clinical efficacy.

Effects of Aripiprazole on Olanzapine Population Pharmacokinetics and Initial Dosage Optimization in Schizophrenia Patients

“…As is known to all, cytochrome P450 (CYP) 2D6 is one of the metabolic enzymes of olanzapine, 21,22 meanwhile CYP2D6 also metabolizes aripiprazole. [23][24][25] Namely, olanzapine and aripiprazole both are CYP2D6 substrates, there be competing interactions. From the present results, we can conclude that aripiprazole competes with olanzapine metabolism, and then reduces olanzapine clearance to a certain extent.…”

“…[17][18][19][20] As is known to all, cytochrome P450 (CYP) 2D6 is one of the metabolic enzymes of olanzapine, 21,22 meanwhile CYP2D6 also metabolizes aripiprazole. [23][24][25] Namely, olanzapine and aripiprazole both are CYP2D6 substrates, there may be competing interactions, influencing olanzapine concentration and clinical treatment outcome such as efficacy and adverse reactions.…”

Drug–drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics

“…The main metabolic pathways of aripiprazole in the liver include dehydrogenation, hydroxylation, and N -dealkylation via the CYP2D6 and CYP3A4 enzymes ( 17 ). However, aripiprazole is metabolized to a lesser extent by the CYP3A4 enzyme, implying that CYP3A4 does not have an appreciable impact on the pharmacokinetics of aripiprazole ( 17 – 19 ).…”

Receptors Involved in Mental Disorders and the Use of Clozapine, Chlorpromazine, Olanzapine, and Aripiprazole to Treat Mental Disorders

“…Scientists report that neuropsychiatric ailments, such as schizophrenia, autism, and Parkinson's disease, are associated with D1Rand D2R-signaling pathways. Therefore, several ligands (medications) were developed that target the two receptors to treat CNS disorders and keep the dopaminergic system constant [42][43][44][45].…”