Abundance and Associated Variations of Cytochrome P450 Drug-Metabolizing Enzymes in the Liver of East Asian Adults: A Meta-Analysis

An, Xiaoxiao; Yu, Yichao; Li, Guofu; Yu, Guo

doi:10.1007/s13318-020-00667-9

Cited by 3 publications

(2 citation statements)

References 28 publications

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“…Table 1 provides a summary of the modeling parameters utilized in the PBPK model ( Dixon et al, 2003 ; Barter et al, 2013 ; Dickinson et al, 2016 ; Pilla Reddy et al, 2018 ; Schwenger et al, 2018 ; Alsmadi et al, 2021 ; An et al, 2021 ; Hashino et al, 2023 ; Pharmaceuticals and Medical Devices Agency PMDA, 2023 ). Rodgers and Rowland, and PK-Sim’s standard methods provided the human tissue distribution and cellular permeability estimate for OSI.…”

Section: Methodsmentioning

confidence: 99%

“…In this study, default liver volumes of 2.38 L for Caucasians, 2.16 L for Japanese, and 1.91 L for Chinese populations were utilized. Additionally, Table 1 presents the abundance of six metabolizing enzymes in different ethnic groups based on literature data from references ( Barter et al, 2013 ; An et al, 2021 ). These enzyme abundances are taken into account to capture potential inter-ethnic variations in OSI metabolism.…”

Section: Methodsmentioning

confidence: 99%

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Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach

Liang,

Zhang,

Xue

et al. 2024

Front. Pharmacol.

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Purpose: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for osimertinib (OSI) to predict plasma trough concentration (Ctrough) and pulmonary EGFRm+ (T790M and L858R mutants) inhibition in Caucasian, Japanese, and Chinese populations. The PBPK model was also utilized to investigate inter-ethnic and inter-patient differences in OSI pharmacokinetics (PK) and determine optimal dosing regimens.Methods: Population PBPK models of OSI for healthy and disease populations were developed using physicochemical and biochemical properties of OSI and physiological parameters of different groups. And then the PBPK models were validated using the multiple clinical PK and drug-drug interaction (DDI) study data.Results: The model demonstrated good consistency with the observed data, with most of prediction-to-observation ratios of 0.8–1.25 for AUC, Cmax, and Ctrough. The PBPK model revealed that plasma exposure of OSI was approximately 2-fold higher in patients compared to healthy individuals, and higher exposure observed in Caucasians compared to other ethnic groups. This was primarily attributed to a lower CL/F of OSI in patients and Caucasian. The PBPK model displayed that key factors influencing PK and EGFRm+ inhibition differences included genetic polymorphism of CYP3A4, CYP1A2 expression, plasma free concentration (fup), albumin level, and auto-inhibition/induction on CYP3A4. Inter-patient PK variability was most influenced by CYP3A4 variants, fup, and albumin level. The PBPK simulations indicated that the optimal dosing regimen for patients across the three populations of European, Japanese, and Chinese ancestry was OSI 80 mg once daily (OD) to achieve the desired range of plasma Ctrough (328–677 nmol/L), as well as 80 mg and 160 mg OD for desirable pulmonary EGFRm+ inhibition (>80%).Conclusion: In conclusion, this study’s PBPK simulations highlighted potential ethnic and inter-patient variability in OSI PK and EGFRm+ inhibition between Caucasian, Japanese, and Chinese populations, while also providing insights into optimal dosing regimens of OSI.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach

Liang,

Zhang,

Xue

et al. 2024

Front. Pharmacol.

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Pooled Analysis of Gastric Emptying in Patients With Obesity: Implications for Oral Absorption Projection

et al. 2021

Clinical Therapeutics

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The Role of CYP3A in Health and Disease

2022

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CYP3A is an enzyme subfamily in the cytochrome P450 (CYP) superfamily and includes isoforms CYP3A4, CYP3A5, CYP3A7, and CYP3A43. CYP3A enzymes are indiscriminate toward substrates and are unique in that these enzymes metabolize both endogenous compounds and diverse xenobiotics (including drugs); almost the only common characteristic of these compounds is lipophilicity and a relatively large molecular weight. CYP3A enzymes are widely expressed in human organs and tissues, and consequences of these enzymes’ activities play a major role both in normal regulation of physiological levels of endogenous compounds and in various pathological conditions. This review addresses these aspects of regulation of CYP3A enzymes under physiological conditions and their involvement in the initiation and progression of diseases.

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Abundance and Associated Variations of Cytochrome P450 Drug-Metabolizing Enzymes in the Liver of East Asian Adults: A Meta-Analysis

Cited by 3 publications

References 28 publications

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach

Exploring inter-ethnic and inter-patient variability and optimal dosing of osimertinib: a physiologically based pharmacokinetic modeling approach

Pooled Analysis of Gastric Emptying in Patients With Obesity: Implications for Oral Absorption Projection

The Role of CYP3A in Health and Disease

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