Translational Model-Informed Dose Selection for Iruplinalkib, a Selective Oral ALK/ROS1 Tyrosine Kinase Inhibitor.

We utilized an integrated approach for model-informed dose selection to predict the recommended phase 2 dose (RP2D) of iruplinalkib, a selective oral ALK and ROS1 tyrosine kinase inhibitor. The efficacy and pharmacokinetics data obtained from ROS1 or ALK-overexpressing cell-derived xenograft models were used for pharmacokinetics pharmacodynamics (PKPD) modeling and calculating human iruplinalkib tumor static concentration (TSC). The plasma concentration-time profile based on pooled clinical data was included in population PK (PopPK) analysis. The steady-state plasma concentration-time profile of iruplinalkib was predicted based on 1000 simulated replicates of the analysis dataset overlaid with data from 54 patients who received iruplinalkib at 120, 180, or 240 mg QD. A two-compartment PopPK model with first-order absorption and linear elimination successfully delineated iruplinalkib PK characteristics in mice, with good precision (relative standard error [RSE] < 30%). TSC in humans, estimated using a modified Simeoni model, was 98 and 78 ng/mL for ROS1-positive and ALK-positive tumors, respectively. A two-compartment PopPK model with first-order absorption and first-order elimination was established based on data collected from previous clinical studies, and the model described iruplinalkib PK properties well (RSE < 30%). Iruplinalkib 180 mg QD was predicted to benefit over 90% of the population and recommended as the RP2D. This dose regimen was further validated by results of advanced clinical trials and ultimately incorporated into the prescribing information as the recommended dosage. A translational model-based approach using integrated preclinical PK/PD and PopPK modeling in patients with non-small cell lung cancer is a reliable method to predict RP2D. Trial Registration: ChiCTR.org.cn number: ChiCTR20170871; ClinicalTrials.gov identifier: NCT03389815; ChinaDrugTrials.org.cn number: CTR20190737.