Implications of inter-correlation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: A case study with repaglinideCitation formats

  • External authors:
  • Kosuke Doki
  • Aleksi Tornio
  • Janne T. Backman

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Implications of inter-correlation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: A case study with repaglinide. / Doki, Kosuke; Darwich, Adam; Achour, Brahim; Tornio , Aleksi ; Backman , Janne T.; Rostami-Hochaghan, Amin.

In: British Journal of Clinical Pharmacology, Vol. 84, No. 5, 05.2018, p. 972–986.

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Doki, Kosuke ; Darwich, Adam ; Achour, Brahim ; Tornio , Aleksi ; Backman , Janne T. ; Rostami-Hochaghan, Amin. / Implications of inter-correlation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: A case study with repaglinide. In: British Journal of Clinical Pharmacology. 2018 ; Vol. 84, No. 5. pp. 972–986.

Bibtex

@article{01deb9fbdb4b45ee8884878c28284f1e,
title = "Implications of inter-correlation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: A case study with repaglinide",
abstract = "Aims:Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolising enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 inter-correlation on the predicted inter-individual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically-based pharmacokinetic (PBPK) modelling.Methods:PBPK modelling and simulation was employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming inter-correlations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict pharmacokinetic parameters in presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study.Results:Coefficient of variation (CV) of oral clearance was 52.5{\%} in the absence of inter-correlation between CYP3A4-CYP2C8 abundances which increased to 54.2{\%} when incorporating inter-correlation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0{\%} in the absence of inter-correlation between enzymes to 43.8{\%} when incorporating inter-correlation: 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 inter-correlation (1.55−77.06) than when incorporating inter-correlation (1.79−25.15), which was closer to clinical observations (2.6−12).Conclusions:The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating inter-correlation led to more consistent estimation of extreme values with those observed in inter-individual variabilities of clearance and DDI. As the inter-correlations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.",
keywords = "inter-individual variability, drug-drug interactions, PBPK model, correlation, repaglinide",
author = "Kosuke Doki and Adam Darwich and Brahim Achour and Aleksi Tornio and Backman, {Janne T.} and Amin Rostami-Hochaghan",
year = "2018",
month = "5",
doi = "10.1111/bcp.13533",
language = "English",
volume = "84",
pages = "972–986",
journal = "British Journal of Clinical Pharmacology",
issn = "0306-5251",
publisher = "John Wiley & Sons Ltd",
number = "5",

}

RIS

TY - JOUR

T1 - Implications of inter-correlation between hepatic CYP3A4-CYP2C8 enzymes for the evaluation of drug-drug interactions: A case study with repaglinide

AU - Doki, Kosuke

AU - Darwich, Adam

AU - Achour, Brahim

AU - Tornio , Aleksi

AU - Backman , Janne T.

AU - Rostami-Hochaghan, Amin

PY - 2018/5

Y1 - 2018/5

N2 - Aims:Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolising enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 inter-correlation on the predicted inter-individual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically-based pharmacokinetic (PBPK) modelling.Methods:PBPK modelling and simulation was employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming inter-correlations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict pharmacokinetic parameters in presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study.Results:Coefficient of variation (CV) of oral clearance was 52.5% in the absence of inter-correlation between CYP3A4-CYP2C8 abundances which increased to 54.2% when incorporating inter-correlation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of inter-correlation between enzymes to 43.8% when incorporating inter-correlation: 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 inter-correlation (1.55−77.06) than when incorporating inter-correlation (1.79−25.15), which was closer to clinical observations (2.6−12).Conclusions:The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating inter-correlation led to more consistent estimation of extreme values with those observed in inter-individual variabilities of clearance and DDI. As the inter-correlations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.

AB - Aims:Statistically significant positive correlations are reported for the abundance of hepatic drug-metabolising enzymes. We investigate, as an example, the impact of CYP3A4-CYP2C8 inter-correlation on the predicted inter-individual variabilities of clearance and drug-drug interactions (DDIs) for repaglinide using physiologically-based pharmacokinetic (PBPK) modelling.Methods:PBPK modelling and simulation was employed using Simcyp Simulator (v15.1). Virtual populations were generated assuming inter-correlations between hepatic CYP3A4-CYP2C8 abundances derived from observed values in 24 human livers. A repaglinide PBPK model was used to predict pharmacokinetic parameters in presence and absence of gemfibrozil in virtual populations, and the results were compared with a clinical DDI study.Results:Coefficient of variation (CV) of oral clearance was 52.5% in the absence of inter-correlation between CYP3A4-CYP2C8 abundances which increased to 54.2% when incorporating inter-correlation. In contrast, CV for predicted DDI (as measured by AUC ratio before and after inhibition) was reduced from 46.0% in the absence of inter-correlation between enzymes to 43.8% when incorporating inter-correlation: 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 inter-correlation (1.55−77.06) than when incorporating inter-correlation (1.79−25.15), which was closer to clinical observations (2.6−12).Conclusions:The present study demonstrates via a systematic investigation that population-based PBPK modelling incorporating inter-correlation led to more consistent estimation of extreme values with those observed in inter-individual variabilities of clearance and DDI. As the inter-correlations more realistically reflect enzyme abundances, virtual population studies involving PBPK and DDI should avoid using Monte Carlo assignment of enzyme abundance.

KW - inter-individual variability

KW - drug-drug interactions

KW - PBPK model

KW - correlation

KW - repaglinide

U2 - 10.1111/bcp.13533

DO - 10.1111/bcp.13533

M3 - Article

VL - 84

SP - 972

EP - 986

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

IS - 5

ER -