A Study on Pharmacokinetics of Bosentan with Systems Modeling, Part 1: Translating Systemic Plasma Concentration to Liver Exposure in Healthy Subjects
- 12 January 2018
- journal article
- research article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Drug Metabolism and Disposition
- Vol. 46 (4), 346-356
- https://doi.org/10.1124/dmd.117.078790
Abstract
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, a new approach has been demonstrated to estimate liver exposure based on observed systemic pharmacokinetics from clinical studies using physiologically-based pharmacokinetic modeling. The prediction has been 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 (Kpuu) is 34.9 with a 95% confidence interval of 4.2 to 50. Drug-drug interaction (i.e., cytochrome P450 (CYP) 3A and 2B6 induction) and inhibition of hepatic transporter (i.e., bile salt export pump (BSEP), multidrug resistance-associated proteins (MRPs), and sodium-taurocholate co-transporting polypeptide (NTCP)) are predicted based on the estimated unbound liver tissue or plasma concentrations. With further validation and refinement, it is concluded that the approach may serve to predict human liver exposure and complement other methods involving tissue biopsy and imaging.Keywords
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