High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4∗16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database

Adachi, Koichiro; Ohyama, Katsuhiro; Tanaka, Yoïchi; Sato, Tasuku; Murayama, Norie; Shimizu, Makiko; Saito, Yoshiro; Yamazaki, Hiroshi

doi:10.1016/j.dmpk.2022.100486

Cited by 9 publications

(21 citation statements)

References 35 publications

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“…The number of patients recorded in the JADER database experiencing adverse drug events between April 2004 and March 2022 associated with celecoxib or diclofenac prescribed alone was investigated in the same manner as that used for atorvastatin cases described previously 9) .…”

Section: Numbers and Types Of Adverse Events With Celecoxib And Diclo...mentioning

confidence: 99%

“…The number of drug regimen adjustments recorded as "reduced" or "discontinued" and the number of adverse event cases were analyzed. The times to the onset of events of interest, such as hepatic disorders after celecoxib or diclofenac administration, were calculated as previously described 9) , and the frequencies and types of adverse events are shown in Table 1. Cumulative incidences of adverse events were evaluated using the Kaplan-Meier method with JMP Pro 13.2.1 (SAS Institute, Cary, NC, USA) and Prism 9 (GraphPad Software, La Jolla, CA, USA).…”

Section: Numbers and Types Of Adverse Events With Celecoxib And Diclo...mentioning

confidence: 99%

“…We focused on investigating events reported in the Japanese Adverse Drug Event Report (JADER) database associated with the prescription of single drugs only 8,9) . Among the various factors underlying the mechanisms related to these adverse events associated with the prescription of celecoxib or diclofenac alone, variations in the in vivo intrinsic clearance of the drug, mediated mainly by P450 enzymes, in these individuals may be a causal factor.…”

Section: Introductionmentioning

confidence: 99%

“…Among the various factors underlying the mechanisms related to these adverse events associated with the prescription of celecoxib or diclofenac alone, variations in the in vivo intrinsic clearance of the drug, mediated mainly by P450 enzymes, in these individuals may be a causal factor. We recently reported that a high virtual hepatic and plasma exposure (generated using pharmacokinetic modeling) in subjects harboring impaired CYP3A4*16 may indicate a causal factor for statin intolerance 9) . The aim of the current study was to estimate virtual hepatic and plasma exposures to celecoxib and diclofenac, as model P450 2C9 substrates, in subjects with impaired CYP2C9.…”

Section: Introductionmentioning

confidence: 99%

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Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome <i>P450 2C9*3</i> Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database

Adachi

Ohyama

Tanaka³

et al. 2023

Biological & Pharmaceutical Bulletin

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The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor. The pharmacokinetically modeled plasma concentrations of celecoxib after an oral 200-mg dose increased in CYP2C9*3 homozygotes: the area under the plasma concentration curve was 4.7-fold higher than that in CYP2C9*1 homozygotes. In patients with CYP2C9*3/*3, the virtual hepatic concentrations of diclofenac after three daily 25-mg doses for a week were 11-fold higher than the plasma concentrations in subjects with CYP2C9*1/*1. The in vivo and in vitro fractions of the victim drug metabolized by a specific polymorphic P450 form is an important determining factor for estimating drug-drug interactions. Virtual hepatic and plasma exposures estimated by pharmacokinetic modeling in patients harboring the impaired CYP2C9*3 allele could represent a causal factor for adverse events induced by celecoxib or diclofenac in a manner similar to that for drug interactions.

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Section: Numbers and Types Of Adverse Events With Celecoxib And Diclo...mentioning

confidence: 99%

Section: Numbers and Types Of Adverse Events With Celecoxib And Diclo...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome <i>P450 2C9*3</i> Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database

Adachi

Ohyama

Tanaka³

et al. 2023

Biological & Pharmaceutical Bulletin

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“…Genetic variations of P450 3A4 and drug interactions between P450 3A substrates/inhibitors may lead to an increased incidence of skeletal muscle or hepatic toxicity of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor atorvastatin (Adachi et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

et al. 2023

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Single-nucleotide substitutions of human flavin-containing monooxygenase 3 (FMO3) identified in the whole-genome sequences of the updated Japanese population reference panel (now containing 38,000 subjects) were investigated. In this study, 2 stop codon mutations, 2 frameshifts, and 43 amino-acid-substituted FMO3 variants were identified. Among these 47 variants, 1 stop codon mutation, 1 frameshift, and 24 substituted variants were already recorded in the National Center for Biotechnology Information database. Functionally impaired FMO3 variants are known to be associated with the metabolic disorder trimethylaminuria; consequently, the enzymatic activities of the 43 substituted FMO3 variants were investigated. Twenty-seven recombinant FMO3 variants expressed in bacterial membranes had similar activities toward trimethylamine N-oxygenation (~75-125%) to that of wild-type FMO3 (98 min -1 ). However, 6 recombinant FMO3 variants (Arg51Gly, Val283Ala, Asp286His, Val382Ala, Arg387His, and Phe451Leu) had moderately decreased (≈50%) activities toward trimethylamine N-oxygenation, and 10 recombinant FMO3 variants (Gly11Asp,

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Pharmacokinetic Models Scaled Up from Humanized Liver Mouse Data Can Account for Drug Monitoring Results of Atomoxetine and Its 4-Hydroxylated andN-Demethylated Metabolites in Pediatric Patients Genotyped for CytochromeP450 2D6

Shimizu,

Uehara,

Ohyama

et al. 2023

Drug Metab Dispos

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Atomoxetine is a cytochrome P450 (P450) 2D6 probe substrate and an approved medicine for attention deficit/hyperactivity disorder. In this humanized liver mouse study, interactions between atomoxetine and the P450 2D6 probe drug paroxetine were observed. Human physiologically based pharmacokinetic (PBPK) models were established by scaling up humanized liver mouse data obtained in the absence or presence of paroxetine. These models could explain the drug monitoring results of atomoxetine and its primary 4-hydroxylated and N-demethylated metabolites in Japanese children aged 8-14 years and could be used to help establish the correct dosage and for the evaluation of clinical outcomes. The results of simple PBPK models (using input parameters that reflected the subjects' small body size and normal or reduced P450 2D6-dependent clearance) were in general agreement with one-point measured plasma concentrations of atomoxetine and its 4-hydroxylated and N-demethylated metabolites in 13 pediatric participants. Unexpectedly high hepatic exposure, possibly in intermediate-metabolizer patients harboring CYP2D6*10 or 2D6*36 alleles, might in part explain the adverse effects of atomoxetine prescribed alone recorded in a Japanese adverse-event database. The steady-state, one-point drug monitoring data from the participants indicated extensive biotransformation of atomoxetine to 4-hydroxyatomoxetine under individually prescribed doses of atomoxetine. These results also suggest that a relatively narrow range of 4-hydroxyatomoxetine and N-desmethylatomoxetine concentration ratios in spot urine and/or plasma samples from pediatric patients could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers compared with the wide range of concentrations of the two primary metabolites and substrate in extensive metabolizers. SIGNIFICANCE STATEMENTValidated simple pharmacokinetic models can predict steady-state plasma concentrations of the approved medicine atomoxetine and its primary metabolites in the majority of pediatric patients. The package insert advises careful dose escalation, especially for poor metabolizers; however, no simple way exists to determine cytochrome P450 (P450) 2D6 phenotypes. A relatively narrow range ratio of 4-hydroxyatomoxetine and N-desmethylatomoxetine in spot urine/plasma samples could be a simple semiquantitative determinant factor for P450 2D6 intermediate metabolizers to optimize or confirm the correct dosage.

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High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4∗16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database

Cited by 9 publications

References 35 publications

Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome <i>P450 2C9*3</i> Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database

Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome <i>P450 2C9*3</i> Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database

Variants of Flavin-Containing Monooxygenase 3 Found in Subjects in an Updated Database of Genome Resources

Pharmacokinetic Models Scaled Up from Humanized Liver Mouse Data Can Account for Drug Monitoring Results of Atomoxetine and Its 4-Hydroxylated andN-Demethylated Metabolites in Pediatric Patients Genotyped for CytochromeP450 2D6

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