Review of Pharmacokinetics and Pharmacogenetics in Atypical Long-Acting Injectable Antipsychotics

Abstract

Over the last two decades, pharmacogenetics and pharmacokinetics have been increasingly used in clinical practice in Psychiatry due to the high variability regarding response and side effects of antipsychotic drugs. Specifically, long-acting injectable (LAI) antipsychotics have different pharmacokinetic profile than oral formulations due to their sustained release characteristics. In addition, most of these drugs are metabolized by CYP2D6, whose interindividual genetic variability results in different metabolizer status and, consequently, into different plasma concentrations of the drugs. In this context, there is consistent evidence which supports the use of therapeutic drug monitoring (TDM) along with pharmacogenetic tests to improve safety and efficacy of antipsychotic pharmacotherapy. This comprehensive review aims to compile all the available pharmacokinetic and pharmacogenetic data regarding the three major LAI atypical antipsychotics: risperidone, paliperidone and aripiprazole. On the one hand, CYP2D6 metabolizer status influences the pharmacokinetics of LAI aripiprazole, but this relation remains a matter of debate for LAI risperidone and LAI paliperidone. On the other hand, developed population pharmacokinetic (popPK) models showed the influence of body weight or administration site on the pharmacokinetics of these LAI antipsychotics. The combination of pharmacogenetics and pharmacokinetics (including popPK models) leads to a personalized antipsychotic therapy. In this sense, the optimization of these treatments improves the benefit–risk balance and, consequently, patients’ quality of life.

The pharmacogenetics of the new-generation antipsychotics – A scoping review focused on patients with severe psychiatric disorders

“…Extensive CYP2D6 metabolizers have a half-time for the elimination of aripiprazole of approximately 75 h, while in poor metabolizers, this parameter reaches 146 h ( 68 ). Aripiprazole and its active metabolite are substrates for P-gp ( 70 ). CYP3A5 and ABCB1 genotypes also have been correlated with differences in the pharmacokinetics of aripiprazole, with potential influence on the ratio of the adverse event ( 71 ).…”

Behind the Curtain: Therapeutic Drug Monitoring of Psychotropic Drugs from a Laboratory Analytical Perspective

“…This also applies to newer LAI formulations, which are usually less water-soluble crystals of underivatized antipsychotics (eg, aripiprazole monohydrate). [38][39][40] The use of drug plasma/serum concentration ranges defined for orally administered antipsychotics has been proposed for long-acting risperidone, paliperidone, flupentixole, and aripiprazole. However, for olanzapine pamoate, pharmacokinetic studies suggest an expected upper limit at half of the upper therapeutic limit defined for oral formulation.…”

Genetic and Epigenetic Basis of Drug-Induced Liver Injury

“…Regarding the CYP2E subfamily, the correlation between the CYP2E1 gene and DILI-AT is a hot spot. There are 11 known polymorphisms of CYP2E1 gene Ins (96), -1566 T>A, -1515 T>G, -1414 C>T, -1295 G>C, -1055 C>T, -1027 T>C, -930 A>G, -807 T>C, -352 A>G, and -333 T>A found in Korean population [30][31][32] . Compared with genotypes including allelic variants, the CYP2E1 rs2031920 variant genotype can lead to higher CYP2E1 activity, resulting in increased levels of hepatotoxic metabolites of anti-tuberculosis drugs (especially isoniazid) 30 (table 2).…”