ORIGINAL ARTICLE The predictive value of ABCB1, ABCG2, CYP3A4/5 and CYP2D6 polymorphisms for risperidone and aripiprazole plasma concentrations and the occurrence of adverse drug reactions C Rafaniello 1,6 , M Sessa 1,6 , FF Bernardi 1,6 , M Pozzi 2 , S Cheli 3 , D Cattaneo 3 , S Baldelli 3 , M Molteni 2 , R Bernardini 4 , F Rossi 1 , E Clementi 2,3 , C Bravaccio 5 , S Radice 3 and A Capuano 1 We investigated in ninety Caucasian pediatric patients the impact of the main polymorphisms occurring in CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. Patients with the CA/AA ABCG2 genotype had a statistically significant lower risperidone plasma concentration/dose ratio (Ct/ds) (P-value: 0.007) and an higher estimated marginal probability of developing metabolism and nutrition disorders as compared to the ABCG2 c.421 non-CA/AA genotypes (P-value: 0.008). Multivariate analysis revealed that the ABCG2 c.421 CA/AA genotype was found associated to a higher hazard (P-value: 0.004) of developing adverse drug reactions classified as metabolism and nutrition disorders. The ABCB1 2677TT/3435TT genotype had a statistically significant lower aripiprazole Ct/ds if compared with patients with others ABCB1 genotypes (P-value: 0.026). Information obtained on ABCB1 and ABCG2 gene variants may result useful to tailor treatments with these drugs in Caucasian pediatric patients. The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.38 INTRODUCTION The increased use of antipsychotics in the pediatric population in Europe in the last decade 1–6 has opened efficacy- and safety- related issues still partially unsolved 7–18 including on the role of genetic factors in modulating efficacy and safety also by altering antipsychotics plasma concentration. 19–26 Cytochrome P450 (CYP)- 2D6 and -3A allelic variants, in particular, were found to alter the metabolic pathways of antipsychotics. 27,28 Specifically, CYP2D6 *3, *4, *5 and *6 alleles were found to be responsible for more than 98% of the CYP2D6 inactive alleles in Caucasians and they resulted associated with a CYP2D6 phenotype with a reduced metabolic functionality. The CYP2D6 gene duplication, instead, was found associated with a CYP2D6 increased metabolism phenotype. 29 Regarding CYP3A4 gene, the CYP3A4*22 allele, which frequency ranged from 3.2 to 6.9% in Caucasians, was found associated with a reduced expression of CYP3A4 messenger ribonucleic acid and with a reduced CYP3A4 metabolic activity. 30 CYP3A5*3, the most frequent allele in Caucasians, was found associated to a loss of protein expression with a consequent reduced pool of the enzyme and alteration of CYP3A-mediated drug metabolism. 30,31 Similarly, allelic variants of ABCB1 and ABCG2 genes were found to influence the plasma concentrations of antipsychotics through an alteration of transport activities performed by their gene products. 32–34 These proteins belong to the ATP-Binding Cassette superfamily, involved in multidrug resistance due to their ability to reduce the concentration of drugs in tissues by increasing efflux from the tissues back to blood. 35 In particular, ABCB1 C3435T and G2677T/A were reported to alter the expression and the activity of P-glycoprotein that in turn was found associated with an altera- tion of absorption and distribution of several drugs, including antipsychotics. 33 ABCG2 c.421 C4A, instead, was found associated with a lower expression levels of this transporter protein for which evidence suggest a potential role on antipsychotics pharmaco- kinetic. 36–38 Evidence on the impact of CYP3A, CYP2D6, ABCB1 and ABCG2 allelic variants on plasma concentrations of antipsychotics is available mainly for adults, while little is known on their impact in the pediatric population, 19–25 despite studies about the ontogeny of CYP3A, CYP2D6, ABCB1 and ABCG2 expression suggest that their role is influenced by age. 39–47 To address this issue we investigated in a Caucasian pediatric population the impact of allelic variants of CYP3A, CYP2D6, ABCB1 and ABCG2 genes on second-generation antipsychotics plasma concentrations, and their association with the occurrence of adverse drug reactions. MATERIALS AND METHODS Study setting This pharmacogenetic sub-study carried out from March 2012 to March 2014 is part of an observational study that investigated the pharmacoki- netic profile, 48 the effectiveness 11 and safety 14 of second-generation 1 Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", Second University of Naples, Naples, Italy; 2 Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy; 3 Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Unit of Clinical Pharmacology, CNR Institute of Neuroscience, University of Milan, Milan, Italy; 4 Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, University of Catania, Catania, Italy and 5 Department of Translational Medical Sciences, Section of Neuropsychiatry, University "Federico II", Naples, Italy. Correspondence: Dr C Rafaniello, Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", Second University of Naples, Via Santa Maria di Costantinopoli 16, Naples 80138, Italy. E-mail: concetta.rafaniello@unicampania.it 6 These authors have equally contributed and served as co-first author in this manuscript. Received 8 February 2017; revised 6 April 2017; accepted 7 June 2017 The Pharmacogenomics Journal (2017) 00, 1 – 9 © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1470-269X/17 www.nature.com/tpj