Incorporating Pharmacological Target-Mediated Drug Disposition (TMDD) in a Whole-Body Physiologically Based Pharmacokinetic (PBPK) Model of Linagliptin in Rat and Scale-up to Human

Abstract

Linagliptin demonstrates substantial nonlinear pharmacokinetics due to its saturable binding to its pharmacological target dipeptidyl peptide 4 (DPP-4), a phenomenon known as target-mediated drug disposition (TMDD). In the current study, we established a novel whole-body physiologically-based pharmacokinetic (PBPK)-TMDD model for linagliptin. This comprehensive model contains plasma and 14 tissue compartments, among which TMDD binding process was incorporated in 9 of them, namely the plasma, kidney, liver, spleen, lung, skin, salivary gland, thymus, and reproductive organs. Our final model adequately captured the concentration-time profiles of linagliptin in both plasma and various tissues in both wildtype rats and DPP4-deficient rats following different doses. The association rate constant (kon) in plasma and tissues were estimated to be 0.943 and 0.00680 nM−1 h−1, respectively, and dissociation rate constant (koff), in plasma and tissues were estimated to be 0.0698 and 0.00880 h−1, respectively. The binding affinity of linagliptin to DPP-4 (Kd) was predicted to be higher in plasma (0.0740 nM) than that in tissue (1.29 nM). When scaled up to a human, this model captured the substantial and complex nonlinear pharmacokinetic behavior of linagliptin in human adults that is characterized by less-than dose-proportional increase in plasma exposure, dose-dependent clearance and volume of distribution, as well as long terminal half-life with minimal accumulation after repeated doses. Our modeling work is not only novel but also of high significance as the whole-body PBPK-TMDD model platform developed using linagliptin as the model compound could be applied to other small-molecule compounds exhibiting TMDD to facilitate their optimal dose selection.

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Funding

This work is partially supported via University of Iowa Pharmaceutics Development Consortium.

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Correspondence to Guohua An.

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Appendix

Appendix

Appendix Fig. 1
figure6

Goodness fit plots for the final PBPK-TMDD modeling for linagliptin observed versus model-predicted in both wildtype and DPP4-deficient rat different tissues after 0.01, 0.1, 0.3, 1, 3, 10, and 50 mg/kg intravenous dose at 72 h. Yellow bars represent predicted linagliptin tissue concentration. Gray bars represent observed linagliptin tissue concentration

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Wu, N., An, G. Incorporating Pharmacological Target-Mediated Drug Disposition (TMDD) in a Whole-Body Physiologically Based Pharmacokinetic (PBPK) Model of Linagliptin in Rat and Scale-up to Human. AAPS J 22, 125 (2020). https://doi.org/10.1208/s12248-020-00481-w

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KEY WORDS

  • linagliptin
  • human scale-up
  • target-mediated drug disposition
  • physiologically-based pharmacokinetic model
  • dipeptidyl peptidase inhibitor