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Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

ABSTRACT: 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. 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. 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. 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.

SUBMITTER: Olsson E

PROVIDER: S-EPMC4468884 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

Olsson Eric E Edman Gunnar G Bertilsson Leif L Hukic Dzana Sudic DS Lavebratt Catharina C Eriksson Sven V SV Ösby Urban U

The primary care companion for CNS disorders 20150219 1

<h4>Objective</h4>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.<h4>Method</h4>There were 113 patients on clozapine treatment recr ...[more]

PMID: 26137357

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Project description:BackgroundOptimal use of lithium involves adjustment of the dose, to keep the plasma level within the narrow, recommended range. Brand-specific prescribing has long been considered critical to achieving this aim, but this is a convention based on very limited data.ObjectivesTo explore the effect of selected demographic and clinical factors on the relationship between lithium dose and plasma level and determine whether there is an independent effect of lithium brand.DesignAnalysis of clinical audit data collected in 2023 as part of a quality improvement programme addressing the use of lithium, conducted by the Prescribing Observatory for Mental Health.MethodsData were collected from clinical records using a bespoke proforma, submitted online and analysed using SPSS.ResultsData were submitted for 4405 patients who had been prescribed solid-dosage formulations of lithium for more than a year. Priadel® was prescribed for 3722 (84%) of these patients, Camcolit® for 112 (2.5%) and the prescription was written generically for 554 (12.5%). Compared with Priadel, where Camcolit was prescribed, the mean daily dose was 10% higher and the mean plasma lithium level was 11% higher. A multivariable analysis was conducted to explore the relationship between selected clinical variables and maintenance lithium dose. This found that in 4213 patients whose most recent plasma lithium level was between 0.3 and 1.19 mmol/L, the variables age, sex, ethnicity, psychiatric diagnosis and the severity of chronic kidney disease were independently associated with dose while the brand of lithium prescribed was not.ConclusionOur findings replicate those of previous studies with respect to the demographic and clinical variables that can be expected to influence lithium dosage in routine clinical practice. This reinforces the need to titrate the dosage for each individual patient, to achieve and maintain the target plasma level. However, the findings suggest that the Priadel and Camcolit brands of lithium are essentially interchangeable.

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Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

Publications

Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

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