A next generation physiologically-based kinetic model for quantitative in vitro to in vivo extrapolation of cisplatin-induced nephrotoxicity in humans

Animal-based toxicity tests inadequately predict human nephrotoxicity, hence the call for human-based new approach methodologies. Nephrotoxic chemicals often accumulate in the proximal tubule as transporters on the polarized membrane of these cells can actively take-up chemicals. The aim of the present study was to develop next generation human physiologically-based kinetic (PBK) models to simulate plasma and kidney concentrations and predict the nephrotoxicity of i.v.-administered cisplatin as the model compound. The PBK models were used to predict nephrotoxic doses of this chemotherapeutic by quantitative in vitro to in vivo extrapolation (QIVIVE) of literature available concentration-response relationships of cytotoxicity in renal cell lines. Two forms of the PBK model were developed: one with a simple single kidney compartment and another including a multi-compartmental kidney that includes organic cation transporter 2 (OCT2)-mediated active renal secretion. Observed single dose of 50 mg/m² lead to nephrotoxicity in 30 % of patients. Using only in vitro and in silico-derived pharmacokinetic parameters, human benchmark dose levels (BMDL)₃₀ values were calculated for all QIVIVE obtained dose-response curves using the maximum concentration in kidney blood or proximal tubule and the area under the concentration-time curve (AUC) in the proximal tubule. Based on the AUC in proximal tubule, the complex form of the model predicts nephrotoxicity in 30 % of patients best, between 23.1 and 65 mg/m². This study provides a case study for next generation risk assessment using PBK models that incorporate active renal secretion to better predict plasma concentration-time profiles are well as in vivo nephrotoxic dose levels.