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Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk

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ABSTRACT

Purpose

To investigate the effect of OATP1B1 genotype as a covariate on repaglinide pharmacokinetics and drug-drug interaction (DDIs) risk using a reduced physiologically-based pharmacokinetic (PBPK) model.

Methods

Twenty nine mean plasma concentration-time profiles for SLCO1B1 c.521T>C were used to estimate hepatic uptake clearance (CLuptake) in different genotype groups applying a population approach in NONMEM v.7.2.

Results

Estimated repaglinide CLuptake corresponded to 217 and 113 μL/min/106 cells for SLCO1B1 c.521TT/TC and CC, respectively. A significant effect of OATP1B1 genotype was seen on CLuptake (48% reduction for CC relative to wild type). Sensitivity analysis highlighted the impact of CLmet and CLdiff uncertainty on the CLuptake optimization using plasma data. Propagation of this uncertainty had a marginal effect on the prediction of repaglinide OATP1B1-mediated DDI with cyclosporine; however, sensitivity of the predicted magnitude of repaglinide metabolic DDI was high. In addition, the reduced PBPK model was used to assess the effect of both CYP2C8*3 and SLCO1B1 c.521T>C on repaglinide exposure by simulations; power calculations were performed to guide prospective DDI and pharmacogenetic studies.

Conclusions

The application of reduced PBPK model for parameter optimization and limitations of this process associated with the use of plasma rather than tissue profiles are illustrated.

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Acknowledgments and DISCLOSURES

The work was funded by a consortium of pharmaceutical companies within the Centre for Applied Pharmacokinetic Research, University of Manchester (http://www.pharmacy.manchester.ac.uk/capkr/).

NT is a recipient of a PhD studentship from University of Manchester and Eli Lilly and Company, Indianapolis, USA.

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  1. Michael Gertz

    Present address: F. Hoffmann-La Roche, Modelling and Simulation, Pharmaceutical Sciences pRED, Basel, Switzerland

Authors and Affiliations

  1. Centre for Applied Pharmacokinetic Research Manchester Pharmacy School, The University of Manchester, Oxford Road, M13 9PT, Manchester, UK

    Michael Gertz, Nikolaos Tsamandouras, Carolina Säll, J. Brian Houston & Aleksandra Galetin

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  1. Michael Gertz
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Correspondence to Aleksandra Galetin.

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Gertz, M., Tsamandouras, N., Säll, C. et al. Reduced Physiologically-Based Pharmacokinetic Model of Repaglinide: Impact of OATP1B1 and CYP2C8 Genotype and Source of In Vitro Data on the Prediction of Drug-Drug Interaction Risk. Pharm Res 31, 2367–2382 (2014). https://doi.org/10.1007/s11095-014-1333-3

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