ArticleBritish journal of clinical pharmacology2018
Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide.
Article in British journal of clinical pharmacology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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12 citing papers in PubMed, 22 citations in OpenAlex.
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- A two-stages global sensitivity analysis by using the δ sensitivity index in presence of correlated inputs: application on a tumor growth inhibition model based on the dynamic energy budget theory.Journal of pharmacokinetics and pharmacodynamics · 2023Article
- Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions: Research Methods and Applications.Metabolites · 2023Review
- Proteomic quantification of receptor tyrosine kinases involved in the development and progression of colorectal cancer liver metastasis.Frontiers in oncology · 2023Article
- A latent variable approach to account for correlated inputs in global sensitivity analysis.Journal of pharmacokinetics and pharmacodynamics · 2021Article
- Utilizing physiologically based pharmacokinetic modeling to predict theoretically conceivable extreme elevation of serum flecainide concentration in an anuric hemodialysis patient with cirrhosis.European journal of clinical pharmacology · 2020Article
- Quantitative Proteomics of Clinically Relevant Drug-Metabolizing Enzymes and Drug Transporters and Their Intercorrelations in the Human Small Intestine.Drug metabolism and disposition: the biological fate of chemicals · 2020Observational
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- Toward a Consensus on Applying Quantitative Liquid Chromatography-Tandem Mass Spectrometry Proteomics in Translational Pharmacology Research: A White Paper.Clinical pharmacology and therapeutics · 2019Article
- Accounting for inter-correlation between enzyme abundance: a simulation study to assess implications on global sensitivity analysis within physiologically-based pharmacokinetics.Journal of pharmacokinetics and pharmacodynamics · 2019Article
- Implications of intercorrelation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: a case study with repaglinide.British journal of clinical pharmacology · 2018Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aimsStatistically significant positive correlations are reported for the abundance of hepatic drug-metabolizing enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 intercorrelation on the predicted interindividual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically based pharmacokinetic (PBPK) modelling.
methodsPBPK modelling and simulation were employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming intercorrelations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict PK parameters in the presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study.
resultsCoefficient of variation (CV) of oral clearance was 52.5% in the absence of intercorrelation between CYP3A4-CYP2C8 abundances, which increased to 54.2% when incorporating intercorrelation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of intercorrelation between enzymes to 43.8% when incorporating intercorrelation: these CVs were associated with 5th/95th percentiles (2.48-11.29 vs. 2.49-9.69). The range of predicted DDI was larger in the absence of intercorrelation (1.55-77.06) than when incorporating intercorrelation (1.79-25.15), which was closer to clinical observations (2.6-12).
conclusionsThe present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating intercorrelation led to more consistent estimation of extreme values than those observed in interindividual variabilities of clearance and DDI. As the intercorrelations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.
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