Objective Our objective was to determine the influence of cytochrome P450 (CYP) 2C9 and CYP2C19 genetic polymorphisms on warfarin dose requirement and metabolic clearance. Methods The study population consisted of 93 Italian outpatients receiving long‐term warfarin anticoagulant therapy (international normalized ratio values, 2‐3), divided into 3 dose groups: low (43.75 mg/wk; n = 24). Steady‐state unbound plasma concentrations of S‐ and R‐warfarin were measured by HPLC and equilibrium dialysis, and corresponding unbound oral clearance (CL_free) values were calculated. Allelic variants of CYP2C9 (CYP2C9*2 and CYP2C9*3) and CYP2C19 (CYP2C19*2) were identified by polymerase chain reaction, followed by restriction enzyme analysis. Results Fifty‐four patients carried no CYP2C9 mutated alleles (*1/*1), 31 carried one (*1/*2, n = 15; and *1/*3, n = 16), and 8 carried two (*2/*2, n = 2; *3/*3, n = 2; and *2/*3, n = 4). Two subjects were homozygous and 19 were heterozygous for the CYP2C19*2 allele variant. The frequencies of CYP2C9 mutated alleles were 72% in the low‐dose group, 36% in the medium‐dose group, and 4% in the high‐dose group; the corresponding mean S‐warfarin CL_free values were 307.5 mL/min, 480.3 mL/min, and 881.3 mL/min. The mean S‐warfarin CL_free values varied significantly among the CYP2C9 genotype groups (P < .0001), although most patients (72%) with no mutated alleles showed S‐warfarin CL_free values in the same range as those carrying mutated alleles (58–777 mL/min). No relationship was found between S‐warfarin CL_free and CYP2C19 genotype or between R‐warfarin CL_free and either CYP2C9 or CYP2C19 genotype. Conclusion CYP2C9 genetic polymorphisms markedly influence warfarin dose requirements and metabolic clearance of the S‐warfarin enantiomer, although nongenetic factors may also contribute to their large interindividual variability. Clinical Pharmacology & Therapeutics (2002) 72, 702–710; doi: 10.1067/mcp.2002.129321

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Abstract: Newer antipsychotics introduced in clinical practice in recent years include clozapine, risperidone, olanzapine, quetiapine, sertindole, ziprasidone, aripiprazole and amisulpride. These agents are subject to drug–drug interactions with other psychotropic agents or with medications used in the treatment of concomitant physical illnesses. Most pharmacokinetic interactions with newer antipsychotics occur at the metabolic level and usually involve changes in the activity of the major drug‐metabolizing enzymes involved in their biotransformation, i.e. the cytochrome P450 (CYP) monooxygenases and/or uridine diphosphate‐glucuronosyltransferases (UGT). Clozapine is metabolized primarily by CYP1A2, with additional contribution by other CYP isoforms. Risperidone is metabolized primarily by CYP2D6 and, to a lesser extent, CYP3A4. Olanzapine undergoes both direct conjugation and CYP1A2‐mediated oxidation. Quetiapine is metabolized by CYP3A4, while sertindole and aripiprazole are metabolized by CYP2D6 and CYP3A4. Ziprasidone pathways include aldehyde oxidase‐mediated reduction and CYP3A4‐mediated oxidation. Amisulpride is primarily excreted in the urine and undergoes relatively little metabolism. While novel antipsychotics are unlikely to interfere with the elimination of other drugs, co‐administration of inhibitors or inducers of the major enzymes responsible for their metabolism may modify their plasma concentrations, leading to potentially significant effects. Most documented metabolic interactions involve antidepressant and anti‐epileptic drugs. Of a particular clinical significance is the interaction between fluvoxamine, a potent CYP1A2 inhibitor, and clozapine. Differences in the interaction potential among the novel antipsychotics currently available may be predicted based on their metabolic pathways. The clinical relevance of these interactions should be interpreted in relation to the relative width of their therapeutic index. Avoidance of unnecessary polypharmacy, knowledge of the interaction profiles of individual agents, and careful individualization of dosage based on close evaluation of clinical response and, possibly, plasma drug concentrations are essential to prevent and minimize potentially adverse drug interactions in patients receiving newer antipsychotics.