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Physiologically based pharmacokinetic model of lapatinib developed in mice and scaled to humans

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Abstract

Lapatinib is an oral 4-anilinoquinazoline derivative that dually inhibits epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This drug is a mere decade old and has only been approved by the FDA for the treatment of breast cancer since 2007. Consequently, the intricacies of the pharmacokinetics are still being elucidated. In the work presented herein, we determined the biodistribution of orally administered lapatinib in mouse plasma, brain, heart, lung, kidney, intestine, liver, muscle and adipose tissue. Using this data, we subsequently developed a physiologically based pharmacokinetic (PBPK) model of lapatinib in mice that accurately predicted the tissue concentrations after doses of 30, 60 and 90 mg/kg. By taking into account interspecies differences in physiology and physiochemistry, we then extrapolated the mouse PBPK model to humans. Our model predictions closely reflected lapatinib plasma pharmacokinetics in healthy subjects. Additionally, we were also able to simulate the pharmacokinetics of this drug in the plasma of patients with solid malignancies by incorporating a decrease in liver metabolism into the model. Finally, our PBPK model also facilitated the estimation of various human tissue exposures to lapatinib, which harmonize with the organ-specific toxicities observed in clinical trials. This first-generation PBPK model of lapatinib can be further improved with a greater understanding of lapatinib absorption, distribution, metabolism and excretion garnered from subsequent in vitro and in vivo studies and expanded to include other pharmacokinetic determinants, including efflux transporters, metabolite generation, combination dosing, etc., to better predict lapatinib disposition in both mouse and man.

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Acknowledgments

We are grateful to Jerry L. Campbell (Center for Human Health Assessment, The Hamer Institutes for Health Sciences, Research Triangle Park, Durham, NC, USA), Conrad Housand (The AEgis Technologies Group, Oshawa, ON, USA) and Robin McDougall (The AEgis Technologies Group, Oshawa, ON, USA) for all of their help and guidance with this project. This work was supported in part by Grant number W81XWH-09-1-0457 from the Department of Defense (DOD) Breast Cancer Research Program (BCRP) of the Office of the Congressionally Directed Medical Research Programs (CDMRP).

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The authors declare that they have no conflict of interest.

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  1. Department of Clinical Sciences, Animal Cancer Center, Colorado State University, Fort Collins, CO, USA

    Susan F. Hudachek & Daniel L. Gustafson

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  1. Susan F. Hudachek
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  2. Daniel L. Gustafson
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Correspondence to Susan F. Hudachek.

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Hudachek, S.F., Gustafson, D.L. Physiologically based pharmacokinetic model of lapatinib developed in mice and scaled to humans. J Pharmacokinet Pharmacodyn 40, 157–176 (2013). https://doi.org/10.1007/s10928-012-9295-8

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