Genetic and Clinical Factors Affecting Plasma Clozapine Concentration

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Objective: To assess (1) the variance of plasma clozapine levels; (2) the relative importance of sex, smoking habits, weight, age, and specific genetic variants of cytochrome P450 1A2 (CYP1A2), uridine diphosphate glucuronosyltransferase 1A4 (UGT1A4), and multidrug resistance protein 1 (MDR1) on plasma levels of clozapine; and (3) the relation between plasma clozapine levels, fasting glucose levels, and waist circumference.

Method: There were 113 patients on clozapine treatment recruited from psychosis outpatient clinics in Stockholm County, Sweden. Patients had genotype testing for single nucleotide polymorphisms: 2 in MDR1, 3 in CYP1A2, and 1 in UGT1A4. Multiple and logistic regression were used to analyze the relations.

Results: There was a wide variation in plasma concentrations of clozapine (mean = 1,615 nmol/L, SD = 1,354 nmol/L), with 37% of the samples within therapeutic range (1,100–2,100 nmol/L). Smokers had significantly lower plasma clozapine concentrations than nonsmokers (P .03). There was a significant association between the rs762551 A allele of CYP1A2 and lower plasma clozapine concentration (P .05). Increased fasting glucose level was 3.7-fold more frequent in CC and CA genotypes than AA genotype (odds ratio = 0.27; 95% confidence interval, 0.10–0.72). There was no significant relation between higher fasting glucose levels, larger waist circumference, and higher clozapine levels.

Conclusions: It is difficult to predict plasma clozapine concentration, even when known individual and genetic factors are considered. Therefore, therapeutic drug monitoring is recommended in patients who are treated with clozapine.

Prim Care Companion CNS Disord 2015;17(1):doi:10.4088/PCC.14m01704