Reply to “Minor Contribution of UGT1A1 Inhibition to Atazanavir‐Related Bilirubin Elevation Supported by Conservative PBPK Modeling and Clinical Data”

We thank Dong and colleagues for their response to our Commentary,1 and for providing greater clarity regarding their PBPK simulations of the bilirubin – atazanavir interaction.2 We wish to emphasize, however, that our Commentary sought primarily to highlight the potential pitfalls associated with the subjective, uncritical use of in vitro kinetic parameters from highly variable and sometimes discrepant datasets as inputs for PBPK model development. In support of their initial studies, the reply by Dong et al. presents appreciably more simulations, including sensitivity analyses with Km and Vmax, which tend to demonstrate this point. As discussed in our Commentary, input selection is an extremely important consideration with bilirubin given the profound dependence of the kinetic parameters for bilirubin glucuronidation (by UGT1A1) and the hepatocellular uptake of bilirubin and its glucuronide conjugates (by OATP1B1/3) on experimental conditions. For example, published Km values for UGT1A1-catalyzed bilirubin glucuronidation span 2-orders of magnitude depending on the enzyme source and the use of optimized vs. nonoptimized experimental conditions. We reiterate the importance of the objective selection of reliable, high-quality input parameters to avoid bias in modeling and data interpretation. The DDI liability of sorafenib as a precipitant of interactions arising from inhibition of UGT1A1 activity warrants clarification. Despite being an extremely potent inhibitor of UGT1A1 (Ki,u 33 nM),3 the increase in SN-38 exposure observed in patients co-administered sorafenib and irinotecan was modest (AUC-R 2.2).4 This is explained by the very high plasma protein binding of sorafenib (fu 0.005) and consequently low unbound blood concentration [Iu], recalling that the magnitude of a drug–drug interaction arising from inhibition of enzyme activity is dependent on the [Iu]/Ki,u ratio.5 The authors thank Professors A. Galetin and J. B. Houston (University of Manchester, U.K.) for their valuable advice. No funding was received for this work. The authors declared no competing interests for this work.