A Study on Pharmacokinetics of Bosentan with Systems Modeling, Part 1: Translating Systemic Plasma Concentration to Liver Exposure in Healthy Subjects

• Published in: Drug metabolism and disposition Vol. 46; no. 4; pp. 346 - 356
• Main Authors: Li, Rui, Niosi, Mark, Johnson, Nathaniel, Tess, David A., Kimoto, Emi, Lin, Jian, Yang, Xin, Riccardi, Keith A., Ryu, Sangwoo, El-Kattan, Ayman F., Maurer, Tristan S., Tremaine, Larry M., Di, Li
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2018; American Society for Pharmacology and Experimental Therapeutics, Inc
• Subjects: ATP-Binding Cassette Transporters - metabolism; Bile; Biopsy; Bosentan; Confidence intervals; Drug interaction; Drug interactions; Drug Interactions - physiology; Exposure; Healthy Volunteers; Hepatocytes - metabolism; Humans; Liver; Liver - metabolism; Mathematical models; Membrane Transport Proteins - metabolism; Modelling; MRP protein; Multidrug resistance; Multidrug Resistance-Associated Proteins - metabolism; Organic Anion Transporters - metabolism; Organic Anion Transporters, Sodium-Dependent - metabolism; Pharmacodynamics; Pharmacokinetics; Pharmacology; Predictions; Proteins; Sensitivity analysis; Sodium; Substrates; Sulfonamides - blood; Sulfonamides - pharmacokinetics; Symporters - metabolism; Toxicity; DILI; BSEP; CI; DDI; MCMC; PBPK; MRP; OATP; ET; RBC; NTCP; P450; PK; PET
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.117.078790

Understanding liver exposure of hepatic transporter substrates in clinical studies is often critical, as it typically governs pharmacodynamics, drug-drug interactions, and toxicity for certain drugs. However, this is a challenging task since there is currently no easy method to directly measure drug concentration in the human liver. Using bosentan as an example, we demonstrate a new approach to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically based pharmacokinetic modeling. The prediction was verified to be both accurate and precise using sensitivity analysis. For bosentan, the predicted pseudo steady-state unbound liver-to-unbound systemic plasma concentration ratio was 34.9 (95% confidence interval: 4.2, 50). Drug-drug interaction (i.e., CYP3A and CYP2B6 induction) and inhibition of hepatic transporters (i.e., bile salt export pump, multidrug resistance-associated proteins, and sodium-taurocholate cotransporting polypeptide) were predicted based on the estimated unbound liver tissue or plasma concentrations. With further validation and refinement, we conclude that this approach may serve to predict human liver exposure and complement other methods involving tissue biopsy and imaging.