Model-Informed Development of a Subcutaneous Formulation of Tislelizumab: Phase 1 Pharmacokinetics in Patients With...

Although tislelizumab is approved across multiple malignancies and dosing schedules, intravenous administration imposes logistical burdens. A subcutaneous formulation may improve convenience and reduce resource demands if comparable exposure is achieved. This study evaluated the pharmacokinetics, bioavailability, and injection-site performance of subcutaneous tislelizumab and used population pharmacokinetic (PopPK) modeling and simulations to support phase 3 dose selection. In the phase 1 BGB-A317-103 study, treatment-naïve patients with locally advanced or metastatic non-small cell lung cancer received tislelizumab via subcutaneous thigh, subcutaneous abdominal, or intravenous administration. A PopPK model was developed with subcutaneous compartments to characterize site-specific absorption and covariate effects. Simulations compared subcutaneous 300 mg every 3 weeks (Q3W) with intravenous 200 mg Q3W regimens to estimate the probability of achieving comparable pharmacokinetic exposure. The PopPK model demonstrated greater bioavailability and lower variability with subcutaneous thigh vs. abdominal administration. Estimated absorption rates were 0.189 1/d for thigh and 0.247 1/d for abdomen, with corresponding bioavailability estimates of 86.6% and 73.1%. The model described absorption and exposure across administration routes and supported the simulation of 1,000 trials. Subcutaneous 300 mg thigh administration achieved pharmacokinetic exposures comparable to intravenous 200 mg across key parameters, including trough concentration and area under the curve (AUC) at Cycle 1 and steady state, whereas abdominal administration showed reduced probability of achieving target exposure thresholds for Cycle 1 AUC. Tislelizumab 300 mg Q3W subcutaneous thigh administration is predicted to provide exposure comparable to intravenous 200 mg Q3W, supporting its selection for phase 3 evaluation. Trial registration: ClinicalTrials.gov identifier: NCT06091943.