Physiologically Based Pharmacokinetic Model of the DPP-4 Inhibitor Linagliptin to Describe its Nonlinear Pharmacokinetics in Humans

Linagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, for type 2 diabetes exhibits nonlinear plasma protein binding in the therapeutic concentration range due to its high affinity binding to the pharmacological target DPP-4, and its pharmacokinetics both in plasma and urine is also nonlinear. The purpose of the present study was to explain the nonlinear pharmacokinetic profiles using a physiologically based pharmacokinetic (PBPK) model with saturable binding of linagliptin to soluble and membrane-bound DPP-4 in blood and organs including kidneys. The model was first fitted to previously reported full-scale plasma concentrations and urinary excretion data at 4 intravenous (iv) dose levels. Additional fitting to the data from 4 oral (po) dose levels was then performed to yield the final iv-po based model including gastrointestinal absorption-associated parameters. Data from [14C]linagliptin mass balance study were also used for optimizing parameters related to enterohepatic circulation. The PBPK model was thus constructed and well describes the nonlinear pharmacokinetic profiles of linagliptin in both plasma and urine, demonstrating that the nonlinear pharmacokinetics are fully explained by its specific binding to target protein. The present study thus introduces the involvement of target-mediated disposition for linagliptin in humans.