A semimechanistic PK/PD model-informed Taxus tablets' development: Accelerating early clinical translation of a...

Taxus chinensis formulation is clinically utilized for the treatment of cancer, while Taxus tablet is expected to be developed as an antitumor drug for early clinical trials. Preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis could minimize ineffective exposure in antitumor clinical trials, but model-informed drug development (MIDD) is rarely used in traditional Chinese medicine. This study applied MIDD to Taxus tablets for optimal dose and schedule and set a traditional Chinese medicine MIDD example. Cytotoxicity assays, flow cytometry, and antitumor efficacy in NCI-H1975 tumor-bearing mice were conducted to generate experimental evidence and PD data, which formed the basis for PD model development. A monoclonal antibody targeting P-glycoprotein shift assays, molecular docking, and PK studies in beagle and tumor-bearing mice were performed to identify the primary PK marker and collect PK data. Additionally, PK consistency was evaluated in humanized P-glycoprotein-expressing rat models. Finally, a PK/PD model was built using concentrations in tumor tissues and simulations were for dose optimization. Taxus extracts exhibited stronger anti-proliferative activity against NCI-H1975 cells than paclitaxel (PTX) alone by inducing cell apoptosis and G2/M cell cycle arrest in NCI-H1975 cells. Taxus tablets (tumor inhibition rate: 79.3%) matched PTX injection (tumor inhibition rate: 64.0%) in efficacy with good tolerance in vivo. PK analysis confirmed PTX as the primary antitumor component of Taxus tablets compared to other taxanes, with about 10% bioavailability and a higher tumor-to-plasma exposure ratio compared with PTX injections (6.41 vs 2.95). Taxus tablet overcame approximately 73.85% P-glycoprotein barriers due to competitive inhibition from taxanes, consistent with P-glycoprotein humanized models. A semimechanistic PK/PD model was constructed using tumor PTX as the PK marker and validated by external data. Model simulations identified 4 mg/kg daily oral administration as the optimal regimen. This study confirms Taxus tablets as an effective oral antitumor agent and successfully constructs a stable PK/PD model using tumor PTX concentrations as the PK marker, which could guide optimal dose and schedule for first in human and provides a traditional Chinese medicine MIDD case. SIGNIFICANCE STATEMENT: Taxus tablets exhibit reliable antitumor efficacy with clarified dose-effect relationships, as human-consistent P-glycoprotein inhibition improved paclitaxel bioavailability and enhanced tumor/plasma exposure. In vitro and in vivo evidence supports a PK/PD model using tumor paclitaxel concentration that avoids pharmacokinetic interactions and offers a new quantitative pharmacology perspective.