Abstract
Introduction: Effective serum level of clozapine ranges from 400 to 600 μg/l. Its main metabolite, norclozapine, is primarily produced by the cytochrome P450 (CYP) 1A2 and 3A4 isoforms. The metabolic ratio (norclozapine/clozapine) usually ranges from 40 to 70%. At standard dose, some individuals with a reduced metabolism may experience overdose leading to dose-dependent adverse reactions.Material and methods: We report the case of a 21-year-old female patient with schizoaffective disorder, treated with 400 mg/day clozapine after slowly increase. Three months after initiation, she presented a tonic–clonic seizure associated with a high plasma level of clozapine. Pharmacogenetic analyses were performed through Next Generation Sequencing to explore polymorphisms of major (CYP3A4/A5, CYP1A2), minor (CYP2C8, CYP2C19, CYP2D6), phase 2 (UGT1A1) enzymes, and transporter (ABCB1) involved in clozapine pharmacokinetic pathways.Results: Mean metabolic ratio (n = 11) was 37% ± 5.4%. The day of the seizure, clozapine level reached 1440 μg/l with a metabolic ratio of 39%. The patient also received diazepam 5 mg/day that has been withdrawn few days before seizure. Other causes of overdose related to lifestyle or pharmacokinetic interaction were ruled out. Pharmacogenenetic results did not suggest any alteration of the major metabolic pathway, but a UGT1A1*28/*28 polymorphism, characteristic of Gilbert syndrome was identified, along with a CYP2D6*1/*3 genotype which results in an intermediate CYP2D6 phenotype.Discussion/Conclusion: Despite extensive phenotypic and genotypic investigations, it is unclear how addition of these two reduced function polymorphisms may have contributed to this overdose. Gilbert syndrome has been associated with high clozapine plasma levels [1,2]. Although CYP2D6 plays only a minor role in clozapine metabolism, the FDA considers it as a gene-drug interaction and suggests dose reduction in CYP2D6 poor metabolizers [3]. Finally, we cannot exclude that diazepam might have acted as a protective agent until it was stopped.References:[1] Erickson-Ridout KK et al. Glucuronidation of the second-generation antipsychotic clozapine and its active metabolite N-desmethylclozapine. Potential importance of the UGT1A1 A (TA)₇TAA and UGT1A4 L48V polymorphisms. Pharmacogenet Genomics. 2012 Aug;22(8):561–76.[2] Stanbridge AJ et al. Clozapine metabolism may be affected by Gilbert’s syndrome: case report and discussion. Pharmacogenet Genomics. 2021 Dec 1;31 (9):221–224.[3] FDA, online, https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations, visited on January 4th, 2023.