Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies conjugated to potent cytotoxic payloads via linkers for cancer treatment. However, the ADCs are also associated with the risk of drug-induced interstitial lung disease (ILD), primarily due to off-target payload distribution. This study aimed to develop a whole-body physiologically based pharmacokinetic and pharmacodynamic (PBPK-PD) model to simultaneously predict the pharmacokinetics, therapeutic efficacy and associated risks of ILD using trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) as model drugs. The model was initially validated in corresponding tumor-bearing mice and subsequently scaled up to breast cancer patients. Plasma concentrations of ADCs and their released payloads as well as progression-free survival (PFS) following treatment with the ADCs were simulated in patients using the developed PBPK-PD model. The results showed that most of the observed plasma concentrations of ADCs and their payloads fell within the 5th-95th percentiles derived from simulations of 1000 virtual patients, with the predicted AUC_0-t and C_max were all within 0.5-fold to 2-fold of the observations. The predicted PFS values were also consistent with clinical observations. Data from Sobol' global sensitivity analysis showed that tumor surface antigen expression levels and the internalization rate of the antigen-ADC complex are the primary factors influencing ADCs distribution. A relationship between payload concentration in lungs and the risk of ILD was also documented, showing that the risk increased with advancing patient age and elevated dosage. All these results give a conclusion that the developed PBPK-PD model may be applied to predict the pharmacokinetics and therapeutical efficacy of T-DXd and SG as well as risk of ILD.

Background/Objectives: SPT-07A, a D-borneol, is currently being developed in China for the treatment of ischemic stroke. We aimed to create a whole-body physiologically-based pharmacokinetic (PBPK) model to predict the pharmacokinetics of SPT-07A in rats, dogs, and humans. Methods: The in vitro metabolism of SPT-07A was studied using hepatic, renal, and intestinal microsomes. The pharmacokinetics of SPT-07A in rats were simulated using the developed PBPK model and in vitro data. Following validation using pharmacokinetic data in rats, the developed PBPK model was scaled up to dogs and humans. Results: Data from hepatic microsomes revealed that SPT-07A was primarily metabolized by UDP-glucuronosyltransferase (UGTs). Glucuronidation of SPT-07A also occurred in the kidney and intestine. The in vitro to in vivo extrapolation analysis showed that hepatic clearance of SPT-07A in rats, dogs, and humans accounted for 62.2%, 87.3%, and 76.5% of the total clearance, respectively. The renal clearance of SPT-07A in rats, dogs, and humans accounted for 32.6%, 12.7%, and 23.1% of the total clearance, respectively. Almost all of the observed concentrations of SPT-07A following single or multi-dose to rats, dogs, and humans were within the 5th–95th percentiles of simulations from 100 virtual subjects. Sensitivity analysis showed that hepatic metabolic velocity, renal metabolic velocity, and hepatic blood flow remarkably affected the exposure to SPT-07A in humans. Dedrick plots were also used to predict the pharmacokinetics of SPT-07A in humans. Prediction accuracy using the PBPK model is superior to that of Dedrick plots. Conclusions: We elucidate UGT-mediated SPT-07A metabolism in the liver, kidney, and intestine of rats, dogs, and humans. The pharmacokinetics of SPT-07A were successfully simulated using the developed PBPK model.