Abstract
Purpose
To evaluate an alternative in vitro system which can provide more quantitatively accurate drug drug interaction (DDI) prediction for 10 protein kinase inhibitors for which DDI risk was over-predicted by inhibition data generated in human liver microsomes (HLM).
Methods
Three cryopreserved human hepatocyte (hHEP) systems: 1) plated hHEPs; 2) hHEPs suspended in Dulbecco’s Modified Eagle Medium (DMEM) and 3) hHEPs suspended in human plasma (plasma hHEPs) were developed to detect CYP3A time dependent inhibition, and the static mechanistic model was used to predict clinical outcomes.
Results
A general trend was observed in the CYP3A inactivation potency (k inact /K I, app ) as HLM > plated > DMEM ≥ plasma hHEPs. Using the static mechanistic model, DDIs predicted using parameters estimated from plated, DMEM and plasma hHEPs had 84, 74 and 95% accuracy (out of 19 clinical interaction studies) within 2-fold of the reported interaction, respectively. They demonstrated significant improvement compared to the DDIs predicted using parameters estimated from HLMs where 58% accuracy was obtained.
Conclusions
Based on 19 DDIs, plasma hHEPs demonstrate a more reliable clinical DDI prediction for 10 protein kinase inhibitors and prototypical CYP3A time dependent inhibitors.
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Abbreviations
- [I] g :
-
The intestinal inhibitor concentration
- [I] h :
-
The hepatic inhibitor concentrations
- DDI:
-
Drug drug interactions
- DMEM:
-
Dulbecco’s Modified Eagle Medium
- fu,mic :
-
Unbound fraction in human liver microsomes
- fu,hep :
-
The non specific binding in the hepatocyte incubation
- f u,p :
-
Unbound fraction in human plasma
- GMFE:
-
The geometric mean-fold error
- hHEPs:
-
Human hepatocytes
- HLM:
-
Human liver microsomes
- IS:
-
Internal standard
- k deg :
-
Degradation rate constant
- K I :
-
Inactivation constant
- K i :
-
Inhibition constant
- K I,app :
-
Apparent inactivation constant
- K i,app :
-
Apparent inhibition constant
- k inact :
-
Maximum inactivation rate constant
- RMSE:
-
The root-mean-square error
- TDI:
-
Time dependent inhibition
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ACKNOWLEDGMENTS AND DISCLOSURES
This study was funded by Genentech (A member of the Roche group). All authors were employees of Genentech when this work was carried out. They have no other conflicts of interest to declare. We would like to thank Dr. Steve Wrighton for his thorough review of this manuscript, and Dr. Jason Halladay for the helpful suggestions.
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Mao, J., Tay, S., Khojasteh, C.S. et al. Evaluation of Time Dependent Inhibition Assays for Marketed Oncology Drugs: Comparison of Human Hepatocytes and Liver Microsomes in the Presence and Absence of Human Plasma. Pharm Res 33, 1204–1219 (2016). https://doi.org/10.1007/s11095-016-1865-9
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DOI: https://doi.org/10.1007/s11095-016-1865-9