Dataset Information

Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

ABSTRACT: 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.

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:ObjectiveOur objective is to document progress in developing personalized therapy with fluoropyrimidine drugs (FPs) to improve outcomes for cancer patients and to identify areas requiring further investigation.BackgroundFPs including 5-fluorouracil (5-FU), are among the most widely used drugs for treating colorectal cancer (CRC) and other gastrointestinal (GI) malignancies. While FPs confer a survival benefit for CRC patients, serious systemic toxicities, including neutropenia, occur in ~30% of patients with lethality in 0.5-1% of patients. While serious systemic toxicities may occur in any patient, patients with polymorphisms in DPYD, which encodes the rate-limiting enzyme for pyrimidine degradation are at very high risk. Other genetic factors affecting risk for 5-FU toxicity, including miR-27a, are under investigation.MethodsLiterature used to inform the text of this article was selected from PubMed.gov from the National Library of Medicine while regulatory documents were identified via Google search.ConclusionsClinical studies to date have validated four DPYD polymorphisms (DPYD*2A, DPYD*13, c.2846A>T, HapB3) associated with serious toxicities in patients treated with 5-FU. Genetic screening for these is being implemented in the Netherlands and the UK and has been shown to be a cost-effective way to improve outcomes. Factors other than DPYD polymorphisms (e.g., miR-27a, TYMS, ENOSF1, p53) also affect 5-FU toxicity. Functional testing for deficient pyrimidine catabolism {defined as [U] >16 ng/mL or [UH2]:[U] <10} is being implemented in France and has demonstrated utility in identifying patients with elevated risk for 5-FU toxicity. Therapeutic drug monitoring (TDM) from plasma levels of 5-FU during first cycle treatment also is being used to improve outcomes and pharmacokinetic-based dosing is being used to increase the percent of patients within optimal area under the curve (AUC) (18-28 mg*h/L) values. Patients maintained in the optimal AUC range experienced significantly reduced systemic toxicities. As understanding the genetic basis for increased risk of 5-FU toxicity becomes more refined, the development of functional-based methods to optimize treatment is likely to become more widespread.

Dataset Information

Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

Publications

Genetic and Clinical Factors Affecting Plasma Clozapine Concentration.

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