Potential Role of Patients’ CYP3A-Status in Clozapine Pharmacokinetics

Abstract

Background:The atypical antipsychotic clozapine is effective in treatment-resistant schizophrenia; however, the success or failure of clozapine therapy is substantially affected by the variables that impact the clozapine blood concentration. Thus, elucidating the inter-individual differences in clozapine pharmacokinetics can facilitate the personalized therapy.Methods:Since a potential role in clozapine metabolism is assigned to CYP1A2, CYP2C19, CYP2D6 and CYP3A enzymes, the association between the patients’ CYP status (CYP genotypes, CYP expression) and clozapine clearance was evaluated in 92 psychiatric patients.Results:The patients’ CYP2C19 or CYP2D6 genotypes and CYP1A2 expression seemed to have no effect on clozapine serum concentration, whereas CYP3A4 expression significantly influenced the normalized clozapine concentration (185.53±56.53 in low expressers vs 78.05±29.57 or 66.52±0.25 (ng/mL)/(mg/kg) in normal or high expressers, P<.0001), in particular that the patients expressed CYP1A2 at a relatively low level. The functional CYP3A5*1 allele seemed to influence clozapine concentrations in those patients who expressed CYP3A4 at low levels. The dose requirement for the therapeutic concentration of clozapine was substantially lower in low CYP3A4 expresser patients than in normal/high expressers (2.18±0.64 vs 4.98±1.40 mg/kg, P<.0001). Furthermore, significantly higher plasma concentration ratios of norclozapine/clozapine and clozapine N-oxide/clozapine were observed in the patients displaying normal/high CYP3A4 expression than in the low expressers.Conclusion:Prospective assaying of CYP3A-status (CYP3A4 expression, CYP3A5 genotype) may better identify the patients with higher risk of inefficiency or adverse reactions and may facilitate the improvement of personalized clozapine therapy; however, further clinical studies are required to prove the benefit of CYP3A testing for patients under clozapine therapy.

Variation in the Response of Clozapine Biotransformation Pathways in Human Hepatic Microsomes to CYP1A2‐ and CYP3A4‐selective Inhibitors

“…The present findings that CYP1A2 was important in norCLZ formation in most livers while CYP3A4 had the dominant role in CLZ N ‐oxide formation are consistent with several earlier reports . To date, most clinical studies have quantified CLZ and, in some cases, norCLZ in serum of schizophrenia patients; with the exception of a recent report, CLZ N ‐oxide has been quantified in relatively few studies . It may now be appropriate to extend routine therapeutic drug monitoring , which is used during the early phase of CLZ therapy, to quantify CLZ and both of its major metabolites in serum.…”

“…Previous studies have implicated human hepatic CYPs 1A2 and 3A4 in the oxidative biotransformation of CLZ . Moreover, in vivo phenotyping with small doses of well‐tolerated CYP substrates has corroborated the clinical relevance of these enzymes in CLZ elimination . Such approaches may assist clinicians in determining the optimal dosage of CLZ in individual patients.…”

“…Decreased elimination may increase serum CLZ concentrations and toxicity while rapid rates of metabolism may lead to subtherapeutic drug concentrations in serum. Thus, it has been suggested that in vivo phenotyping with well‐tolerated CYP substrates may be useful in dosage optimization with CLZ and other antipsychotic agents .…”

Exploratory Analysis of Rare and Novel Variants in Mexican Patients Diagnosed with Schizophrenia and Dementia

“…CYP3A4*20 is an allele previously identified in the Brazilian population 114 , and it has been found at high allele frequency in the Spanish population (minor allele frequency = 0.012) 115 , but at low frequency in other European populations. This allele has been reported to affect the metabolism of clozapine, also associated with treatment-resistant SCZ 116 .…”

The Effects of Co-prescription of Pantoprazole on the Clozapine Metabolism

“…CLZ underlies hepatic metabolism by various cytochrome P450 (CYP) isoenzymes, predominantly by CYP1A2. Additionally, CYP2C19, CYP3A4 and CYP2D6 are involved in the metabolism to a varying extent [3]. CYP2C19 and CYP3A4 account for approximately 35 % of the CLZ metabolism at therapeutic concentrations [4].…”