Population Pharmacokinetic/Pharmacodynamic Model of Clozapine for Characterizing the Relationship Between Accumulated Exposure and PANSS Scores in Patients With Schizophrenia

Shang, Dewei; Li, Lijun; Wang, Xipei; Yao, Wen; Ren, Yupeng; Guo, Wei; Li, Wen-Biao; Li, Liang; Zhou, Tianyan; Lu, Wei; Wang, Chuanyue

doi:10.1097/ftd.0000000000000014

Cited by 18 publications

(50 citation statements)

References 22 publications

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“…e number of concentration readings (observations) ranged from 22 to 1617, with a median of 410, and the median observation per patient was 3. e daily dose was reported in nine studies with a median of 291 mg/day (134-540 mg/day) [15-19, 21, 22, 25, 26]. Most of the included studies used NONMEM software for population pharmacokinetic model [18,[20][21][22][23][24][25][26].…”

Section: Analysis Methods Used In Pharmacokinetics Modelmentioning

confidence: 99%

“…After abstract and title scanning, 15 articles were retained for final evaluation. A total of 12 studies [15][16][17][18][19][20][21][22][23][24][25][26] published between 1987 and 2019 were included in this review, as demonstrated in Figure 1. Study characteristics of the included publications, samples, and concentrations are summarized in Table 1.…”

Section: Literature Searchmentioning

confidence: 99%

“…In eleven of the included studies, the clozapine absorption was best described as first order [15,16,[18][19][20][21][22][23][24][25][26]. e absorption rate was estimated in six of the included studies with a median of 0.69 h − 1 (0.037-2.26 h − 1 ) [16, 19-21, 25, 26], while it was fixed to a certain value from the literature in four of the studies [22][23][24]26]. A one-compartment model was the best structural model that described the population pharmacokinetics of clozapine in most of the studies [16, 18-23, 25, 26], while the two-compartment model was reported in only three studies [15,17,24].…”

Section: Structural Pharmacokinetics Modelmentioning

confidence: 99%

“…e absorption rate was estimated in six of the included studies with a median of 0.69 h − 1 (0.037-2.26 h − 1 ) [16, 19-21, 25, 26], while it was fixed to a certain value from the literature in four of the studies [22][23][24]26]. A one-compartment model was the best structural model that described the population pharmacokinetics of clozapine in most of the studies [16, 18-23, 25, 26], while the two-compartment model was reported in only three studies [15,17,24]. e median reported volume of distribution (Vd) was 508 L (272-1290 L) [15,16,18,19,21,23] for clozapine and 624 L for norclozapine [23].…”

Section: Structural Pharmacokinetics Modelmentioning

confidence: 99%

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Population Pharmacokinetics of Clozapine: A Systematic Review

Albitar

Harun

Zainal

et al. 2020

BioMed Research International

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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.

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Section: Analysis Methods Used In Pharmacokinetics Modelmentioning

confidence: 99%

Section: Literature Searchmentioning

confidence: 99%

Section: Structural Pharmacokinetics Modelmentioning

confidence: 99%

Section: Structural Pharmacokinetics Modelmentioning

confidence: 99%

See 2 more Smart Citations

Population Pharmacokinetics of Clozapine: A Systematic Review

Albitar

Harun

Zainal

et al. 2020

BioMed Research International

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“…Modeling and study simulation have been used to characterize the association between drug exposure and efficacy in studies of antipsychotic therapy for schizophrenia. 15,[17][18][19][20] The goal of the present analysis was to characterize the dose-response profile of lurasidone in the treatment of patients with bipolar depression to inform clinical dosing decisions and identify patient subgroups that might benefit from dose adjustments. Using data from registration studies of lurasidone in patients with bipolar depression, a population exposure-response model was developed to characterize Montgomery-Åsberg Depression Rating Scale (MADRS) 21 score change over time as a function of lurasidone dose.…”

Section: Introductionmentioning

confidence: 99%

Lurasidone Dose Response in Bipolar Depression: A Population Dose-response Analysis

Chapel¹,

Chiu

Hsu

et al. 2016

Clinical Therapeutics

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Population PK/PD model of tacrolimus for exploring the relationship between accumulated exposure and quantitative scores in myasthenia gravis patients

Chen

Yao

Yin

et al. 2023

CPT Pharmacom & Syst Pharma

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Tacrolimus is an important immunosuppressant used in the treatment of myasthenia gravis (MG). However, the population pharmacokinetic (PK) characteristics together with the exposure-response of tacrolimus in the treatment of MG remain largely unknown. In this study, we aimed to develop a population PK/ pharmacodynamic (PK/PD) model of tacrolimus in patients with MG, in order to explore the relationships among tacrolimus dose, exposure, and its therapeutic efficacy. The genotype of CYP3A5, Osserman's classification, and status of thymus, as well as demographic characteristics and other biomarkers from laboratory testing were tested as covariate, and simulations were performed based on the final model. The population PK model was described using a one-compartment model with first-order elimination and fixed absorption parameters. CYP3A5 genotype significantly influenced the apparent clearance, and total protein (TP) influenced the apparent volume of distribution as covariates. The quantitative MG scores were characterized by the cumulated area under curve of tacrolimus in a maximum effect function. Osserman's classification was a significant covariate on the initial score of patients with MG. The simulations demonstrated that tacrolimus showed an unsatisfying effect possibly due to insufficient exposure in some patients with MG. A starting dose of 2 mg/d and even higher dose for patients with CYP3A5 *1/*1 and *1/*3 and lower TP level were required for the rapid action of tacrolimus. The population PK/PD model quantitatively described the relationships among tacrolimus dose, exposure, and therapeutic efficacy in patients with MG, which could provide reference for the optimization of tacrolimus dosing regimen at the individual patient level.

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Population Pharmacokinetic/Pharmacodynamic Model of Clozapine for Characterizing the Relationship Between Accumulated Exposure and PANSS Scores in Patients With Schizophrenia

Abstract: The PK/PD model can describe the clinical response as measured by decreasing PANSS score during treatment and may be useful for optimizing the dose regimen for individual patients.

Cited by 18 publications

References 22 publications

Population Pharmacokinetics of Clozapine: A Systematic Review

Population Pharmacokinetics of Clozapine: A Systematic Review

Lurasidone Dose Response in Bipolar Depression: A Population Dose-response Analysis

Population PK/PD model of tacrolimus for exploring the relationship between accumulated exposure and quantitative scores in myasthenia gravis patients

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