Retrospective use of PBPK modelling to understand a clinical drug–drug interaction between dextromethorphan and GSK1034702

Abstract

1. In a clinical trial, a strong drug–drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI.

2. In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702. PBPK models were populated with the in vitro parameters and DDI simulations conducted and compared to the observed data from a clinical study with DM and GSK1034702.

3. GSK1034702 was a potent direct and metabolism-dependent inhibitor of human CYP2D6, with inhibition parameters of: IC₅₀=1.6 μM, K_inact = 3.7 h⁻¹ and K_I = 0.8 μM. Incorporating these data into PBPK models predicted a DDI after repeat, but not single, 5 mg doses of GSK1034702.

4. The DDI observed with repeat administration of GSK1034702 (5 mg) can be attributed to metabolism-dependent inhibition of CYP2D6. Further, in vitro data were generated and several potential mechanisms proposed to explain the interaction observed following a single dose of GSK1034702.

Keywords:

• CYP2D6
• dextromethorphan
• drug–drug interaction
• GSK1034702
• in silico modelling
• metabolism-dependent inhibition

Acknowledgements

We would like to thank, Carole Shardlow for discussions around SimCYP™ modelling and Maxine Taylor for expert discussions about the fluorescent assays.

Declaration of interest

This study was funded by GlaxoSmithKline (GSK). The authors are employees and shareholders of GSK and declare no competing interests.