Influence of polymorphism in the CYP1A2, the UGT1A4 and the POR gene on olanzapine serum concentrations and clinical outcome

Abstract

Olanzapine is one of the most widely prescribed antipsychotic drugs. Large interindividual variations of serum concentration have been documented. Differences in activity of drug metabolizing enzymes may substantially contribute to these variations. Genotyping for mutations influencing enzyme activity may be useful for dose optimization and identification of high risk patients. Therefore, we investigated the influence of polymorphisms in the CYP1A2 gene (*1D,*1F), the UGT1A4 gene (*3) and in the POR gene (rs2302429) on olanzapine serum concentrations and clinical outcome in a naturalistic study with 98 Caucasian inpatients. Our results for the first time clearly indicate that carriers of the delT-allele develop significantly higher dose corrected olanzapine serum concentrations (heterozygous, n = 5, +65%, homozygous, n = 3, +115%), independent of the confounding factors age, sex, baseline weight and concomitant CYP1A2 inducers (ANCOVA, p = 0.004). The other genotypes studied revealed no significant influence on olanzapine serum concentrations. For clinical outcome only the CYP1A2*1D polymorphism indicated a significant correlation for adverse drug reactions (r2= 0.478, p = 0.020). This effect was found despite the majority (98%) of patients displayed concentrations in or below the therapeutic range (20 – 80 ng/mL) which was probably due to dose optimization following TDM. Further studies are needed before genotype-based dosage may be recommended for clinical use in olanzapine therapy.