An International Adult Guideline for Making Clozapine Titration Safer by Using Six Ancestry-Based Personalized Dosing Titrations, CRP, and Clozapine Levels

Abstract

This international guideline proposes improving clozapine package inserts worldwide by using ancestry-based dosing and titration. Adverse drug reaction (ADR) databases suggest that clozapine is the third most toxic drug in the United States (US), and it produces four times higher worldwide pneumonia mortality than that by agranulocytosis or myocarditis. For trough steady-state clozapine serum concentrations, the therapeutic reference range is narrow, from 350 to 600 ng/mL with the potential for toxicity and ADRs as concentrations increase. Clozapine is mainly metabolized by CYP1A2 (female non-smokers, the lowest dose; male smokers, the highest dose). Poor metabolizer status through phenotypic conversion is associated with co-prescription of inhibitors (including oral contraceptives and valproate), obesity, or inflammation with C-reactive protein (CRP) elevations. The Asian population (Pakistan to Japan) or the Americas’ original inhabitants have lower CYP1A2 activity and require lower clozapine doses to reach concentrations of 350 ng/mL. In the US, daily doses of 300–600 mg/day are recommended. Slow personalized titration may prevent early ADRs (including syncope, myocarditis, and pneumonia). This guideline defines six personalized titration schedules for inpatients: 1) ancestry from Asia or the original people from the Americas with lower metabolism (obesity or valproate) needing minimum therapeutic dosages of 75–150 mg/day, 2) ancestry from Asia or the original people from the Americas with average metabolism needing 175–300 mg/day, 3) European/Western Asian ancestry with lower metabolism (obesity or valproate) needing 100–200 mg/day, 4) European/Western Asian ancestry with average metabolism needing 250–400 mg/day, 5) in the US with ancestries other than from Asia or the original people from the Americas with lower clozapine metabolism (obesity or valproate) needing 150–300 mg/day, and 6) in the US with ancestries other than from Asia or the original people from the Americas with average clozapine metabolism needing 300–600 mg/day. Baseline and weekly CRP monitoring for at least four weeks is required to identify any inflammation, including inflammation secondary to clozapine rapid titration.

Genomic stratification of clozapine prescription patterns using schizophrenia polygenic scores

“…All the AUC values were calculated exclusively on the CLOZUK2 individuals to take advantage of the self-reported ethnicity information only available for this sample. This has been considered an important predictor for clozapine dose optimization (47) and is not always directly comparable to genetic ancestry estimates.…”

An international clozapine titration guideline to increase its safety and move forward on the route started by German-speaking psychiatrists in the 1960s

“…A recent international guideline proposed that clozapine metabolism can be measured by the dose needed to reach the minimum therapeutic range of the plasma concentration of 350 ng/ml. As clozapine metabolism is influenced by: (1) ancestry groups, (2) sex-smoking subgroups, and (3) presence/absence of poor metabolizer (PM) status based on genetic status, personal variables (e.g., obesity) or environmental variables (e.g., oral contraceptives), these 3 levels of variables determine maintenance dose and titration speed [ 5 ].…”

“…Two other causes of death were more concerning: (1) myocarditis with 539 deaths and relative lethality of 11.7% (539/4586) and (2) pneumonia with 2077 deaths and relative lethality of 29.7% (2077/6983). To prevent myocarditis and aspiration pneumonia during clozapine titration, the international titration guideline uses (1) 6 personalized titrations and (2) weekly C-reactive protein (CRP) measures [ 5 ]. Pneumonia occurring during clozapine maintenance may be frequent [ 8 ] but clozapine may only contribute 1/3 of the risk while TRS may contribute 2/3 [ 9 ]…”

“…In 1972, clozapine-induced fever in the absence of any concomitant infection was mentioned in a German article and German-speaking psychiatrists described: (1) an approximate prevalence of 5%, (2) occurring between the 5th and 20th days after initiation, and (3) frequently associated with increased erythrocyte sedimentation rate (ESR). Contemporary knowledge reveals that fever is part of the syndrome of clozapine-induced inflammation which develops when the titration is too fast for the metabolism of that specific patient [ 4 , 5 ]. When clozapine was later introduced in the US, a 5% rate of benign hyperthermia was considered normal during clozapine titration and was believed to spontaneously resolve, but in severe cases stopping and restarting would be required [ 4 ].…”

“…The FDA required almost no pharmacokinetic studies in 1989. In 1994, Swedish researchers described: (1) cytochrome P450 1A2 (CYP1A2) as the main metabolic pathway leading to norclozapine and (2) fluvoxamine as an extremely powerful inhibitor while carbamazepine was a powerful inducer [ 5 ]. Tobacco smoking is a CYP1A2 inducer while estrogens are inhibitors, so CYP1A2 activity is influenced by sex-smoking subgroups; female non-smokers had the lowest activity and male smokers the highest.…”