Predicting In Vivo Target Occupancy (TO) Profiles via Physiologically Based Pharmacokinetic-TO Modeling of Warfarin Pharmacokinetics in Blood: Importance of Low Dose Data and Prediction of Stereoselective Target Interactions.

Wooin Lee, Min-Soo Kim, Jiyoung Kim, Yasunori Aoki, Yuichi Sugiyama

Drug metabolism and disposition: the biological fate of chemicals 2023 Sep

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Warfarin is well recognized for its high-affinity and capacity-limited binding to the pharmacological target and undergoes target-mediated drug disposition. Here, we developed a physiologically based pharmacokinetic (PBPK) model that incorporated saturable target binding and other reported hepatic disposition components of warfarin. The PBPK model parameters were optimized by fitting to the reported blood pharmacokinetic (PK) profiles of warfarin with no stereoisomeric separation after oral dosing of racemic warfarin (0.1, 2, 5, or 10 mg) using the Cluster Gauss-Newton method (CGNM). The CGNM-based analysis yielded multiple "accepted" sets for six optimized parameters, which were then used to simulate the warfarin blood PK and in vivo target occupancy (TO) profiles. When further analyses examined the impact of dose selection on uncertainty in parameter estimation by the PBPK modeling, the PK data from 0.1 mg dose (well below target saturation) was important in practically identifying the target binding-related parameters in vivo. When stereoselective differences were incorporated for both hepatic disposition and target interactions, our PBPK modeling predicted that R-warfarin (of slower clearance and lower target affinity than S-warfarin) contributes to TO prolongation after oral dosing of racemic warfarin. Our results extend the validity of the approach by which the PBPK-TO modeling of blood PK profiles can yield TO prediction in vivo (applicable to the drugs with targets of high affinity and abundance and limited distribution volume via nontarget interactions). Our findings support that model-informed dose selection and PBPK-TO modeling may aid in TO and efficacy assessment in preclinical and clinical phase 1 studies. SIGNIFICANCE STATEMENT: The current physiologically based pharmacokinetic modeling incorporated the reported hepatic disposition components and target binding of warfarin and analyzed the blood pharmacokinetic (PK) profiles from varying warfarin doses, practically identifying target binding-related parameters in vivo. By implementing the stereoselective differences between R- and S-warfarin, our analysis predicted the role of R-warfarin in prolonging overall target occupancy. Our results extend the validity of analyzing blood PK profiles to predict target occupancy in vivo, which may guide efficacy assessment. Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.

Citation

Wooin Lee, Min-Soo Kim, Jiyoung Kim, Yasunori Aoki, Yuichi Sugiyama. Predicting In Vivo Target Occupancy (TO) Profiles via Physiologically Based Pharmacokinetic-TO Modeling of Warfarin Pharmacokinetics in Blood: Importance of Low Dose Data and Prediction of Stereoselective Target Interactions. Drug metabolism and disposition: the biological fate of chemicals. 2023 Sep;51(9):1145-1156