Lead Investigator: Hiroyuki Kusuhara, University of Tokyo
Title of Proposal Research: Assessment of the drug-drug interactions risks of drugs based on the clinical data of the plasma biomarkers
Vivli Data Request: 7835
Funding Source: Japan Society for the Promotion of Science (JSPS)
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Concomitant use of multiple drugs can increase the risk of drug drug interactions (DDI) that alter exposure of either or both drugs in the body, and thereby influencing drug effects. To avoid harmful DDI in clinical settings is one of the major concerns in drug development. Mathematical model approaches have greatly advanced the prediction of DDI magnitude. The plasma biomarkers have emerged to capture DDI risks of the drugs in humans. The time profiles of the biomarker following drug administration is informative to capture the risk of DDI of the drug. We have proposed a simple method to estimate the parameter of the drugs essential for DDI simulation using the mathematical models based on clinical data of the biomarker. This study focused on glecaprevir which was reported to alter the plasma biomarker for DDI in the exposure dependent manner in healthy subjects. The DDI risk of glecaprevir will be analyzed using our mathematical approach.
Statistical Analysis Report:
The plasma concentrations of glecaprevir, coproporphyrin I (CP-I) and CP-III determined in the same subject will be subjected to the analysis. According to the our calculation method (Mochizuki T et al. Clin Transl Sci., 2022), we will calculate the inhibition constant of glecaprevir for organic anion transporting polypeptide 1B1 (OATP1B1) in each subject using the plasma concentrations of glecaprevir and CP-I. Briefly, the maximum change in the plasma concentrations of CP-I and CP-III from baseline values will be defined using the observed data. The inhibition constant of glecaprevir will be calculated using the plasma concentration of glecaprevir at time t when the maximum change in the plasma concentrations of CP-I and CP-III from baseline values was observed. Physiologically-based pharmacokinetic model will be used to describe the plasma concentration time profiles of CP-I with or without glecaprevir treatments. Then, the inhibition constants estimated by the two methods will be compared with the corresponding parameter determined in vitro to support the consistence of clinically determined parameter and corresponding inhibition constant determined in vitro. We will not conduct any statistical analysis to draw the conclusion for this study.
Handling missing values: Missing data will be excluded.
Requested Studies:
A Comparison of the Bioavailability of Experimental Glecaprevir/Pibrentasvir Formulations with Glecaprevir/Pibrentasvir Film-Coated Bilayer Tablets in Healthy Adult Subjects
Data Contributor: AbbVie
Sponsor ID: M15-540
Summary of Results:
This report examines the inhibitory effects of glecaprevir, a direct-acting antiviral agent used in the treatment of hepatitis C, on OATP1B1-mediated transport.
Ki,app values of glecaprevir were estimated using the CmaxR method. This method utilizes the maximum CP-I concentration ratio observed after administration of the OATP1B1 inhibitor and the corresponding plasma concentration of the inhibitor at that time1. The ratio of CP-I or CP-III concentration after glecaprevir administration (CmaxR) was calculated relative to the concentration at time 0 (predose). Using the glecaprevir concentration (Cdrug) at the time (Tmax) when the ratio reaches its maximum value (CmaxR), assuming predominant contribution of OATP1B1 to the elimination of CP-I and CP-III from the systemic circulation.
Ki,app=Cdrug at Tmax /(CmaxR-1) Eq.q
Please note that that if additional concentrations fall within a 3% difference from the maximum value, their corresponding ratios are also selected, and geometric mean values were considered as representative value in the subject. Geometric mean values and 90% confidence of intervals of Ki,app were calculated with regard to the total concentration in the plasma.
CmaxR method was applied to estimate Ki,app of glecaprevir. Using the CmaxR method, similar Ki,app estimates were obtained regardless of the formulation. After the correction of the unbound fraction of glecaprevir in human plasma (0.025), Ki,app was close to the previously reported values (17 nM2). We conducted in vitro inhibition studies to determine IC50 values of glecaprevir. Glecaprevir serves as inhibitor of OATP1B1 in HEK293 cells stably expressing OATP1B1 and human hepatocytes. IC50 value of glecaprevir was assessed using CP-I and pitavastatin as probe substrate for OATP1B1-mediated uptake. However, the IC50 value of glecaprevir in the previous report (17 nM) could not be reproduced in this study.