Population Pharmacokinetics of Clozapine: A Systematic Review

Abstract

Background and Objective. Clozapine is a second-generation antipsychotic drug that is considered the most effective treatment for refractory schizophrenia. Several clozapine population pharmacokinetic models have been introduced in the last decades. Thus, a systematic review was performed (i) to compare published pharmacokinetics models and (ii) to summarize and explore identified covariates influencing the clozapine pharmacokinetics models. Methods. A search of publications for population pharmacokinetic analyses of clozapine either in healthy volunteers or patients from inception to April 2019 was conducted in PubMed and SCOPUS databases. Reviews, methodology articles, in vitro and animal studies, and noncompartmental analysis were excluded. Results. Twelve studies were included in this review. Clozapine pharmacokinetics was described as one-compartment with first-order absorption and elimination in most of the studies. Significant interindividual variations of clozapine pharmacokinetic parameters were found in most of the included studies. Age, sex, smoking status, and cytochrome P450 1A2 were found to be the most common identified covariates affecting these parameters. External validation was only performed in one study to determine the predictive performance of the models. Conclusions. Large pharmacokinetic variability remains despite the inclusion of several covariates. This can be improved by including other potential factors such as genetic polymorphisms, metabolic factors, and significant drug-drug interactions in a well-designed population pharmacokinetic model in the future, taking into account the incorporation of larger sample size and more stringent sampling strategy. External validation should also be performed to the previously published models to compare their predictive performances.

The relationship between plasma clozapine concentration and clinical outcome: a cross‐sectional study

“…7 The CLZ C/D ratio depends on CLZ clearance, which is primarily metabolized by cytochrome P450 (CYP) 1A2. 33 Variant CYP1A2 allele frequencies associated with poor metabolization are more common in Japanese (23.4%) and Asians (21.0-26.7%) than in Caucasians (0.8-4.0%). [34][35][36] Thus, differences in variant CYP1A2 allele frequencies between ethnic groups may explain differences in CLZ clearance.…”

Physiologically-based pharmacokinetic model for clozapine in Korean patients with schizophrenia

“…Clozapine is an atypical antipsychotic drug that belongs to the tricyclic dibenzodiazepine group [ 1 2 ]. This drug is generally used to the treatment of schizophrenia, especially for patients who are intolerant or refractory to the side effects of typical antipsychotic drugs [ 2 3 ]. Clozapine has a lower risk of undesired neurological effects and may ameliorate some negative symptoms compared to other antipsychotic drugs [ 1 3 ].…”

“…This drug is generally used to the treatment of schizophrenia, especially for patients who are intolerant or refractory to the side effects of typical antipsychotic drugs [ 2 3 ]. Clozapine has a lower risk of undesired neurological effects and may ameliorate some negative symptoms compared to other antipsychotic drugs [ 1 3 ]. However, large interindividual variations in plasma clozapine levels at the same dose have been reported [ 4 5 ].…”

Population Pharmacokinetic Modeling of Cyclosporine Among Malaysian Renal Transplant Patients: An Evaluation of Methods to Handle Missing Doses in Conventional Drug‐Monitoring Data

“…Population PK modeling is a useful tool that can be used to estimate the PK parameters of a drug in a population as well as the factors affecting those parameters 9 . Furthermore, when combined with Bayesian forecasting technique, dose adjustment can be guided by a few concentration readings of the drug 10 …”