(M-080) Development of a Simeprevir PBPK Model to Describe Changes in Coproporphyrin-I, an Endogenous OATP1B Biomarker, in Subjects with HCV

Kota Toshimoto, PhD – N/A, Astellas Pharma Inc.; Jan Snoeys, PhD – N/A, Janssen Research and Development; Shinji Yamazaki, PhD – N/A, Certara UK, Ltd.; Yuichi Sugiyama, PhD – Distinguished Professor, Josai International University

[Objectives] Evaluation of drug-drug interaction potency using endogenous substances is useful for efficient drug development.[1] Since OATP1B is involved in the active hepatic uptake of many drugs, the impact of new chemical entities on OATP1B activity should be assessed. Assessing the effects of drugs on blood levels of OATP1B endogenous substrates in subjects with hepatic impairment requires an understanding of not only drug-endogenous substrate interactions but also disease-endogenous substrate interactions. This study aims to quantitatively analyze the effect of anti-HCV drug simeprevir on blood levels of coproporphyrin-I in subjects with hepatic impairment using the PBPK model.

[Methods] Impacts of simeprevir dosing on blood coproporphyrin-I concentrations in subjects with HCV were analyzed using the PBPK model. The previously developed PBPK models of simeprevir and coproporphyrin-I were used. A total of 6 virtual clinical studies of the actual clinical trial size were conducted using predefined inhibitory constant of simeprevir against OATP1B. Monte Carlo simulation was performed to consider reduced hepatic OATP1B and CYP3A4 expression levels reported in subjects with HCV and their inter-individual variability.

[Results] Blood coproporphyrin-I concentrations were in a similar range around 0.6 nmol/L when the simeprevir blood concentration were below 2000 ng/mL, and then increased up to 6 nmol/L at the simeprevir blood concentration range from 2000 to 30000 ng/mL in the actual clinical trial. All virtual clinical studies adequately predicted this trend. Our simulations showed that blood concentrations of both simeprevir and coproporphyrin-I tended to be higher in subjects with severe hepatic impairment (severe fibrosis and cirrhosis), due to low drug clearances and potent OATP1B inhibition by simeprevir.[2]

[Conclusions] Our analysis reveals that not only OATP1B inhibition by simeprevir but also decreases in expression levels of hepatic OATP1B and CYP3A4 due to progression of liver fibrosis can affect the blood levels of coproporphyrin-I in subjects with HCV. The PBPK model coupled with Monte Carlo simulation can provide quantitative insights into the complex drug-endogenous biomarker-disease interaction.

Citations: [1] Yoshikado T et al. PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3. CPT Pharmacometrics Syst Pharmacol. 2018 Nov;7(11):739-747.
[2] Nakayama S et al. Physiologically-based pharmacokinetic modeling for investigating the effect of simeprevir on concomitant drugs and an endogenous biomarker of OATP1B. CPT Pharmacometrics Syst Pharmacol. 2023 Oct;12(10):1461-1472.