Effect of Hepatic Impairment on OATP1B Activity: Quantitative Pharmacokinetic Analysis of Endogenous Biomarker and Substrate Drugs

Abstract

Hepatic impairment (HI) is known to modulate drug disposition and may lead to elevated plasma exposure. The aim of this study was to quantitate the in vivo OATP1B-mediated hepatic uptake activity in populations with varying degrees of HI. First, we measured baseline levels of plasma coproporphyrin-I, an endogenous OATP1B biomarker, in an openlabel, parallel cohort study in adult subjects with normal liver function and mild, moderate, and severe HI (n = 24, 6/ cohort). The geometric mean plasma concentrations of coproporphyrin-I were 1.66-fold, 2.81-fold (P < 0.05), and 7.78fold (P < 0.0001) higher in mild, moderate, and severe impairment than those healthy controls. Second, we developed a dataset of 21 OATP1B substrate drugs with HI data extracted from literature. Median disease-to-healthy plasma area under the curve (AUC) ratios for substrate drugs were ~ 1.4, 3.0, and 6.4 for mild, moderate, and severe HI, respectively. Additionally, significant linear relationship was noted between AUC ratios of substrate drugs without and with coadministration of rifampin, a prototypic OATP1B inhibitor, and AUC ratios in moderate (P < 0.01) and severe (P < 0.001) HI. Third, a physiologically-based pharmacokinetic model analysis was conducted with 10 substrate drugs following estimation of relative OATP1B functional activity in virtual disease population models using coproporphyrin-I data and verification of substrate models with rifampin drug-drug interaction data. This approach adequately predicted plasma AUC change particularly in moderate (9 of 10 within 2-fold) and severe (5 of 5 within 2-fold) HI. Collective findings indicate progressive reduction, by as much as 90-92%, in OATP1B activity in the HI population.

Biomarkers Come of Age in Clinical Pharmacology

“…Expanding on the use of biomarkers for predicting DDIs, Lin et al 5 . in their paper entitled “Effect of Hepatic Impairment on OATP1B1 Activity: Quantitative Pharmacokinetic Analysis of Endogenous Biomarker and Substrate Drugs,” describe the use of biomarkers in predicting the effect of hepatic impairment on the activity of OATP1B.…”

“…Whereas Rodrigues 4 and Lin et al 5 focus on the use of circulating biomarkers of transporters to predict transporter activity changes either through DDIs or human disease, transporter activity may also be modified by genetic polymorphisms. For example, OATP1B1 activity is modulated by several reduced function genetic polymorphisms.…”

“…Expanding on the use of biomarkers for predicting DDIs, Lin et al 5 in their paper entitled "Effect of Hepatic Impairment on OATP1B1 Activity:…”

Characterization of Elimination Pathways and the Feasibility of Endogenous Metabolites as Biomarkers of Organic Anion Transporter 1/3 Inhibition in Cynomolgus Monkeys

“…DMD Fast Forward. Published on April 14, 2023as DOI: 10.1124 at ASPET Journals on April 30, 2023 dmd.aspetjournals.org Downloaded from selective biomarker of OATP1B (Lai et al, 2016;Lin et al, 2022;Mochizuki et al, 2022). Other endogenous metabolites, including pyridoxic acid (PDA) and homovanillic acid (HVA), have been discovered through metabolomic analysis and may serve as biomarkers of Oat1/3 activities in monkeys.…”

Development of 4‐Pyridoxic Acid PBPK Model to Support Biomarker‐Informed Evaluation of OAT1/3 Inhibition and Effect of Chronic Kidney Disease

“…10 Several PBPK models for endogenous biomarkers have already been developed, verified, and applied to estimate the in vivo transporter inhibitory potential of selected inhibitors, 9,11 understand the impact of transporter genotype on endogenous biomarkerinformed DDI assessment, 12 and disease-related changes in biomarker levels. 13,14 Thus far, most of these applications have been for DDI with coproporphyrin I (CP-I), an endogenous biomarker for OATP1B1/3. 9,15,16 In addition to DDI applications, Takita et al 13 extended the CP-I PBPK modeling to predict the increased CP-I baseline in chronic kidney disease (CKD) and rationalize the increased extent of rifampicin-CP-I interaction in patients with CKD vs. healthy subjects.…”