The Elimination Rate after Clozapine Overdose in Chinese Schizophrenia Patients: A Population Pharmacokinetics Model Study

Li, A.-N.; Dong, Fan; He, Jiali; Shang, Dewei; Guo, Wei; Li, W.-B.; Lü, Wei; Wang, Chuanyue

doi:10.1055/s-0035-1554672

Cited by 6 publications

(9 citation statements)

References 19 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%

“…e reported model structure, pharmacokinetic parameters, and covariates tested and retained in the final model are summarized in Table 2. 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].…”

Section: Structural Pharmacokinetics Modelmentioning

confidence: 99%

“…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]. Elimination was best described as first order in six of the included studies [16,19,20,22,25,26] with a median clearance (Cl) value of 30.3 L/h (14.4-45.2 L/h) for clozapine (n � 8) and 46.3 L/h (32.7-58.9 L/h) for norclozapine (n � 4). Model variability, error, and validation are summarized in Table 3.…”

Section: Structural Pharmacokinetics Modelmentioning

confidence: 99%

“…Model variability, error, and validation are summarized in Table 3. In eight of the studies, interindividual variability (IIV) was modeled using the exponential error model [18,[20][21][22][23][24][25][26]. e reported median IIV median (range) for clozapine Cl and Vd were 43.3% (27.1-60.8%) (n � 7) and 65.7% (10-131.5%) (n � 5), respectively, while for norclozapine Cl and Vd are 47.2% (42.1-60.25%) (n � 4) and 75.6% [23], respectively.…”

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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