Minor Contribution of <scp>UGT1A1</scp> Inhibition to Atazanavir‐Related Bilirubin Elevation Supported by Conservative <scp>PBPK</scp> Modeling and Clinical Data

Drs Miners and Polasek highlighted challenges in the in vitro UGT and transporter assays for bilirubin.1 We acknowledge these challenges, which had been considered in our physiologically based pharmacokinetic (PBPK) modeling.2 We agree that there is a lack of confidence in the in vitro–in vivo extrapolation for UGTs and transporters, that is, optimized in vitro assays may still not represent in vivo conditions. Therefore, a middle-out modeling approach was employed. The in vitro/optimized parameters of relevant pathways underwent thorough validation, with most simulated results falling within 0.8–1.25-fold of observed clinical values. It was suggested that the Km value of UGT1A1-mediated unconjugated bilirubin (UB) metabolism could be >17-fold lower, whereas the Vmax value could be >4-fold higher.1 However, sensitivity analyses indicated that applying lower Km or higher Vmax values would predict smaller contribution of UGT1A1 inhibition to the total bilirubin (TB) elevation following atazanavir administration (Figure 1). This is because the faster the metabolism, the less impact by the same magnitude of inhibition. Also, OATP1B1/3 and UGT1A1 pathways function in tandem and compete for the role of rate-limiting step of UB elimination. When the metabolic rate of UGT1A1 increases, the hepatic uptake is further reinforced as the rate-limiting step. Additionally, our model did not underpredict the effect of UGT1A1 polymorphism on the baseline TB levels (Figure 1), suggesting a low risk of underpredicting the role of UGT1A1 in UB elimination. Our original models were adjusted to further minimize the risk of underpredicting the contribution of UGT1A1 inhibition (Figure 1). However, UGT1A1 inhibition remains a minor contributor to the TB elevation in the adjusted simulations (Figure 1; UGT1A1 inhibition alone vs. all interaction pathways: atazanavir alone, 28% vs. 102%; atazanavir/ritonavir, 69% vs. 379%). The conclusion reached from the PBPK modeling was also consistent with clinical data from bilirubin-sorafenib3 (Figure 1) and dolutegravir-atazanavir4 (Figure 1) interaction studies.2 Notably, sorafenib is one of the strongest UGT1A1 inhibitors in vitro and clinically,5 whereas it increased baseline TB levels by < 33%.3 As atazanavir/ritonavir (300/100 mg q.d.) and sorafenib (400 mg b.d.) exhibit comparable UGT1A1 inhibition potential (Css,max,u/IC50,u, 2.77 vs. 2.18; Css,avg,u/IC50,u, 1.15 vs. 1.51),2 UGT1A1 inhibition is unlikely to be the primary TB elevation mechanism. We also agree that the low drug–drug interaction risk of regorafenib and sorafenib (AUC ratios were no more than 2.25) as high-affinity UGT1A1 inhibitors1 suggests that UGTs, as high-capacity enzymes, present a low interaction risk with either low- or high-affinity inhibitors. This study was funded by AstraZeneca. J.D., P.S., W.T., D.Z., D.W.B., and M.N. are employees of AstraZeneca and may hold stock ownership, options, and/or interests in the company. All other authors declared no competing interests for this work.