Analysis of Clozapine Use and Safety by Using Comprehensive National Data From the Japanese Clozapine Patient Monitoring Service

Inada, Keiichi; Oshibuchi, Hidehiro; Ishigooka, Jun; Nishimura, Kazuhiko

doi:10.1097/jcp.0000000000000904

Cited by 23 publications

(39 citation statements)

References 22 publications

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“…A dosing study with >3,000 samples from the Japanese clozapine database described a mean dose of 186 mg/day. [20] In a survey of 117 Indian psychiatrists, Shrivastava and Shah [21] indicated that almost all (86%) of their patients were stabilized on clozapine doses lower than 300 mg/day. A recent Asian review described clozapine daily dosing in single samples from several different countries.…”

Section: The Evidence From Clozapine Dosing In Asian Countriesmentioning

confidence: 99%

Do Asian Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Overview

León

Rajkumar

Kaithi³

et al. 2020

Indian Journal of Psychological Medicine

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Since 1997, studies have found that Asians need lower clozapine doses than Caucasians. Caucasians with average clozapine metabolism may need from 300 to 600 mg/day to reach the therapeutic range (350 ng/ml). Thus, serum clozapine concentration-to-dose (C/D) ratios typically range between 0.60 (male smokers) and 1.20 (female non-smokers). A 2019 systematic review of clozapine levels demonstrated weighted mean C/D ratios of 1.57 in 876 East Asians and 1.07 in 1147 Caucasians (P <.001). In Asian countries, average clozapine doses are lower than 300 mg/day. After sex and smoking stratification in 5 Asian samples with clozapine concentrations, the clozapine dose required to reach 350 ng/ml in female non-smokers ranged from 145 to 189 mg/day and in male smokers, from 259 to 294 mg/day. Thus, in Asian patients with

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Section: The Evidence From Clozapine Dosing In Asian Countriesmentioning

confidence: 99%

Do Asian Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Overview

León

Rajkumar

Kaithi³

et al. 2020

Indian Journal of Psychological Medicine

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“…Despite its efficacy with TRS, the use of CLZ is significantly restricted by severe side effects such as CLZ-induced agranulocytosis (CIA)/CLZ-induced granulocytopenia (CIG) (CIAG), which is rare but potentially life threatening. CIAG events are observed in approximately 1% (for CIA) and 3% (for CIG) of CLZ-treatment patients, although the prevalence of CIA differs between populations (Caucasian: .3%.9%; Asian: greater than 1%; Japanese: 1.1%) (6)(7)(8)(9)(10)(11).…”

mentioning

confidence: 99%

Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population

Takeo

Ikeda

Mushiroda

et al. 2016

Biological Psychiatry

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“…In these models, we did not include the health state related to death and sepsis, because no case has been reported in such conditions after the CPMS started in Japan [12] or very low mortality (0.013%) based on the meta-analysis [13]. Moreover, we did not consider the possibility of CLZ discontinuation based on the WBC cutoff (<3000/mm 3 ), because this "WBC count" definition was not a common reason for discontinuation (in such cases, the ANC usually decreased to 1500/mm 3 ) [13].…”

Section: Methodsmentioning

confidence: 99%

“…The outcome included the mean cost-per-patient and QALYs-per-patient for the calculation of the ICER over a 10-year time period. In particular, in Japan, the mean age of the patients at the start of CLZ treatment was 40.6 years [12], and antipsychotics were recommended to be continued. Thus, we assumed that patients with TRS receive CLZ treatment for at least 10 years, if tolerated.…”

Section: Population Model Structure and Parametersmentioning

confidence: 99%

“…The utility for patients undergoing CLZ treatment was set at 0.693 [7] and that for patients undergoing substitute treatment was set at 0.560 [7]. The utility derived from CIAG was not accounted for in this analysis, because the mortality rate was extremely low, and the median treatment duration of CIAG was 4.5 days as observed in Japan [12].…”

Section: Cost Estimates and Utilities (Supplementary Table 3)mentioning

confidence: 99%

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Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK

et al. 2021

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Pharmacogenetics/pharmacogenomics have enabled the detection of risk of human leukocyte antigen (HLA) variants for clozapine-induced agranulocytosis/granulocytopenia (CIAG). To apply this evidence to the clinical setting, we compared the cost-effectiveness of the proposed “HLA-guided treatment schedule” and the “current schedule” being used in Japan and the United Kingdom (UK) (absolute neutrophil count (ANC) cutoff at 1500/mm3); in the “HLA-guided treatment schedules,” we considered a situation wherein the HLA test performed before clozapine initiation could provide “a priori information” by detecting patients harboring risk of HLA variants (HLA-B*59:01 and “HLA-B 158T/HLA-DQB1 126Q” for Japanese and Caucasian populations, respectively), a part of whom can then avoid CIAG onset (assumed 30% “prevention rate”). For the primary analysis, we estimated the incremental cost-effectiveness ratio (ICER) of “HLA-guided treatment schedule” and “current schedule” used in Japan and the UK, using a Markov model to calculate the cost and quality-adjusted life years (QALYs) over a 10-year time period. Furthermore, as an explorative analysis, we simulated several situations with various ANC cutoffs (1000/mm3 and 500/mm3) and plotted the cost/QALYs for each option to identify the best, or estimate the next best candidate option applicable in actual clinical settings. The primary probabilistic analysis showed that the “HLA-guided treatment schedule” was more cost effective than the “current schedule”; the ICER was £20,995 and £21,373 for the Japanese and the UK populations, respectively. Additional simulation revealed that the treatment option of ANC cutoff at 500/mm3 without HLA screening was the most cost-effective option; however, several options may be candidates to break away from the “current schedule” of ANC cutoff at 1500/mm3. Owing to its cost-effectiveness, we propose such pharmacogenetic-guided/pharmacogenomic-guided clozapine treatment for use in the real-world setting, which provides key information for optimization of clinical guidelines for high-risk patients for gradual change of clozapine treatment schedule under the safety consideration.

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Analysis of Clozapine Use and Safety by Using Comprehensive National Data From the Japanese Clozapine Patient Monitoring Service

Abstract: The data obtained in this study, particularly regarding the incidence of clozapine-induced adverse events, will enable the optimal and safe use of clozapine in Japanese patients with treatment-resistant schizophrenia.

Cited by 23 publications

References 22 publications

Do Asian Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Overview

Do Asian Patients Require Only Half of the Clozapine Dose Prescribed for Caucasians? A Critical Overview

Pharmacogenomic Study of Clozapine-Induced Agranulocytosis/Granulocytopenia in a Japanese Population

Cost effectiveness of pharmacogenetic-guided clozapine administration based on risk of HLA variants in Japan and the UK

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