Physiologically Based Pharmacokinetic Model to Predict Drug-Drug Interactions With the Antibody-Drug Conjugate Trastuzumab Deruxtecan - PubMed
3 hours ago
- #PBPK modeling
- #Antibody-drug conjugate
- #Drug-drug interaction
- The study developed a physiological based pharmacokinetic (PBPK) model for the antibody-drug conjugate Trastuzumab Deruxtecan (T-DXd) to predict drug-drug interactions (DDIs) involving its payload DXd.
- DXd is eliminated through hepatic uptake via OATP1B1/3, metabolism by CYP3A, biliary excretion via P-glycoprotein and breast cancer resistance protein, and urinary excretion.
- In clinical DDI studies, co-administration with strong inhibitors like ritonavir or itraconazole resulted in only a 1.2-fold increase in DXd exposure, indicating minimal clinical impact.
- The PBPK model accurately simulated T-DXd and DXd pharmacokinetics, identifying biliary excretion as the main elimination pathway for DXd, followed by urinary excretion and metabolism.
- The model suggests potential utility for evaluating DDIs with future DXd-containing ADCs and predicting interactions in various scenarios and specific populations.