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Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction

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ABSTRACT

Purpose

To evaluate 26 marketed oncology drugs for time-dependent inhibition (TDI) of cytochrome P450 (CYP) enzymes. Evaluate TDI-positive drugs for potential to generate reactive intermediates. Assess clinical drug–drug interaction (DDI) risk using static mechanistic models.

Methods

Human liver microsomes and CYP-specific probes were used to assess TDI in a dilution shift assay followed by generation of KI and kinact. Reactive metabolite trapping studies were performed with stable label probes. Static mechanistic model was used to predict DDI risk using a 1.25-fold AUC increase as a cut-off for positive DDI.

Results

Negative TDI across CYPs was observed for 13/26 drugs; the rest were time-dependent inhibitors of, predominantly, CYP3A. The kinact/KI ratios for 11 kinase inhibitors ranged from 0.7 to 42.2 ml/min/μmol. Stable label trapping agent–drug conjugates were observed for ten kinase inhibitors. DDI predictions gave no false negatives, one true negative, four false positives and three true positives. The magnitude of DDI was overestimated irrespective of the inhibitor concentration selected.

Conclusions

13/26 oncology drugs investigated showed TDI potential towards CYP3A, formation of reactive metabolites was also observed. An industry standard static mechanistic model gave no false negative predictions but did not capture the modest clinical DDI potential of kinase inhibitors.

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Abbreviations

AUC:

area under the curve

Cav :

average plasma concentration

Cmax :

maximum plasma concentration

CYP:

cytochrome P450

DDI:

drug–drug interaction

HLM:

human liver microsomes

LC:

liquid chromatography

MS/MS:

tandem mass spectrometry

NME:

new molecular entity

PBPK:

physiologically based pharmacokinetic modeling

TDI:

time-dependent inhibition

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ACKNOWLEDGMENTS & DISCLOSURES

We thank Dr Cornelis ECA Hop for encouragement to investigate these oncology drugs and members of Genentech DMPK for valuable discussions.

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Authors and Affiliations

  1. Department of Drug Metabolism and Pharmacokinetics, Genentech Inc., 1 DNA Way, MS412A, South San Francisco, California, 94080, USA

    Jane R. Kenny, Sophie Mukadam, Chenghong Zhang, Suzanne Tay & S. Cyrus Khojasteh

  2. Department of Pharmaceutics, University of Washington, Seattle, USA

    Carol Collins

  3. Center for Applied Pharmacokinetic Research School of Pharmacy and Pharmaceutical Sciences, The University of Manchester, Manchester, UK

    Aleksandra Galetin

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  1. Jane R. Kenny
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  2. Sophie Mukadam
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  3. Chenghong Zhang
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Correspondence to Jane R. Kenny.

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This work was presented in part at the PSW AAPS meeting, 2010, New Orleans.

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Kenny, J.R., Mukadam, S., Zhang, C. et al. Drug–Drug Interaction Potential of Marketed Oncology Drugs: In Vitro Assessment of Time-Dependent Cytochrome P450 Inhibition, Reactive Metabolite Formation and Drug–Drug Interaction Prediction. Pharm Res 29, 1960–1976 (2012). https://doi.org/10.1007/s11095-012-0724-6

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  • DOI: https://doi.org/10.1007/s11095-012-0724-6

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