High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers

Chopra, Nitin; Ruan, Changgeng; McCollum, Betsy; Ognibene, Judy; Shelton, Charles; León, José de

doi:10.1016/j.rcp.2018.07.002

Cited by 7 publications

(6 citation statements)

References 75 publications

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“…Supplementary Figures S1 [62] and S2 [122] illustrate this variability in both clozapine and total C/D ratios in two cases with extreme metabolism explained in Supplementary Box S17 [62,122]. Supplementary Figure S1 [62] describes a clozapine PM with a mean minimum therapeutic dose of 90 mg/day based on 17 TDMs but, using individual TDMs, the minimum therapeutic dose ranged from 66 mg/day to 121 mg/day.…”

Section: Use Of a Single Therapeutic Drug Monitoring In Predicting The Clozapine Maintenance Dosementioning

confidence: 99%

“…Supplementary Figure S1 62 describes a clozapine PM with a mean minimum therapeutic dose of 90 mg/day based on 17 TDMs but, using individual TDMs, the minimum therapeutic dose ranged from 66 mg/day to 121 mg/day. Supplementary Figure S2 122 describes the case of an obese US smoker with a mean minimum therapeutic dose of 443 mg/day based on 17 TDMs but, using individual TDMs, the minimum therapeutic dose ranged from 353 mg/day to 565 mg/day.…”

Section: Clozapine Titrationmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Use Of a Single Therapeutic Drug Monitoring In Predicting The Clozapine Maintenance Dosementioning

confidence: 99%

Section: Clozapine Titrationmentioning

confidence: 99%

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

et al. 2021

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“…CYP3a4 is the highest common isoform metabolizing the widest varieties of drugs and other xenobiotics [29,31]. Different combination mechanisms and factors could affect the CYP expression in liver.…”

Section: Figure 4kidney Tissues Of Group a Show Normal Glomeruli (White Arrows) Normal Renal Tubules (Black Arrows) With Intact Well Orgamentioning

confidence: 99%

Hepatorenal Effects of Diclofenac and Ciprofloxacin in Rats

Abdelgadir

Alzaidi

Ramady³

et al. 2021

AJFSFM

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The toxic effect of diclofenac (DCF) sodium and Ciprofloxacin (CIP) on gene expression of cytochrome P450 oxidase (CYPs) and the histology of liver and kidney of male albino rat has been evaluated in this study. DCF and CIP were chosen since they are inhibitors for specific CYP enzymes. Thirty-five adult male albino rats were divided into 7 groups of 5 animals each (A, B, C, D, E, F and G) and were treated orally with drugs for 21 consecutive days. Group A served as the control while B and C were treated with 5.3, 10.6 mg/kg body weight (bw) DCF sodium and groups D and E were treated with 40 and 80 mg/kg bw CIP, respectively. Groups F and G were treated with a mixture of the low and the high doses of both drugs, respectively. Both drugs significantly downregulated the mRNA expression of CYP1a2, CYP3a4 and CYP2c9. They caused hepatorenal histological changes. In the liver, massive fibrosis, necrosis, inflammatory cell infiltration with hemorrhages and hydrophilic degeneration have been observed. A massive tissue injury with glomerular and tubular damages due to sever necrosis, degeneration of concomitant inflammatory cells and blood vessels congestion have been shown in renal tissues. Although DCF and CIP are still used as therapeutic drugs, their use should be limited as their chronic administration induces a toxic effect on human health.

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“…131 The use of olanzapine and quetiapine C/D ratios in clinical practice is just starting. 132 Most other second-generation antipsychotic TDM science is too underdeveloped to firmly establish therapeutic ranges. 126 Until recently, antipsychotic TDM held no interest for pharmaceutical companies and was only studied by independent investigators with limited funding, who frequently used naturalistic designs from TDM outpatient databases that offered limited access to clinical information.…”

Section: Future Studies Of Tdm Based On Other Antipsychotics and Non-mentioning

confidence: 99%

“…136 Carbamazepine does not follow linear kinetics due to auto-induction. 132 Valproate TDM is severely neglected and very complicated since the total serum valproate concentrations do not follow linear kinetics due to protein displacement 137 and its auto-induction has received almost no attention. 138 Most TDM experts will probably agree that we are very far from being able to use serum TDM to diagnose nonadherence in patients taking antidepressants or mood stabilizers.…”

Section: Future Studies Of Tdm Based On Other Antipsychotics and Non-mentioning

confidence: 99%

<p>Self-Report for Measuring and Predicting Medication Adherence: Experts’ Experience in Predicting Adherence in Stable Psychiatric Outpatients and in Pharmacokinetics</p>

Cuevas

Leon

2020

PPA

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Poor adherence to appropriately prescribed medication is a global challenge for psychiatrists. Prior Studies: Measuring adherence is complicated. In our recent three-country naturalistic study including more than 1000 patients and their adherence to multiple medication prescriptions at the same time, patients' self-report of adherence to each specific drug was the only practical option for measuring adherence. Systematic literature reviews provide inconsistent results for sociodemographic, clinical and medication variables as predictors of adherence to psychiatric drugs. Our studies over the last 10 years in relatively stable psychiatric outpatients have shown that some self-reported health beliefs had consistent, strong effects and a better predictive role. Three dimensions of these health beliefs are characteristics of the individual: 1) attitudes toward psychiatric medication such as pharmacophobia (fear of taking drugs or medicines), 2) health locus of control (the belief patients have about who or what agent determines the state of their health), 3) psychological reactance (an emotional reaction in direct contradiction to rules or regulations that threaten or suppress certain freedoms in behavior). They can be measured by the Patient Health Beliefs Questionnaire on Psychiatric Treatment. The attitude toward each specific medication can be measured by the necessity-concern framework and summarized as the presence or absence of skepticism about that drug. After 25 years conducting pharmacokinetic studies in psychiatric drugs, particularly antipsychotics, we have limited understanding of how to use blood levels to predict the effects of non-adherence or to establish it. Expert Opinion on Future Studies: Future studies to predict adherence should include the inpatient setting and explore insight. Studying the pharmacokinetics associated with nonadherence in each psychiatric drug is a major challenge. Medication adherence is a complex and dynamic process changing over time in the same patient. Personalizing adherence using psychological or pharmacological variables are in their initial stages.

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High Doses of Drugs Extensively Metabolized by CYP3A4 Were Needed to Reach Therapeutic Concentrations in Two Patients Taking Inducers

Cited by 7 publications

References 75 publications

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

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

Hepatorenal Effects of Diclofenac and Ciprofloxacin in Rats

<p>Self-Report for Measuring and Predicting Medication Adherence: Experts’ Experience in Predicting Adherence in Stable Psychiatric Outpatients and in Pharmacokinetics</p>

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