Quantitative Prediction of OATP‐Mediated Drug‐Drug Interactions With Model‐Based Analysis of Endogenous Biomarker Kinetics

Abstract

Quantitative prediction of the magnitude of transporter‐mediated clinical drug‐drug interactions (DDIs) solely from in vitro inhibition data remains challenging. The objective of the present work was to analyze the kinetic profile of an endogenous biomarker for organic anion‐transporting polypeptides 1B (OATP1B), coproporphyrin I (CPI), and to predict clinical DDIs with a probe OATP1B substrate (pravastatin) based on “in vivo” inhibition constants (Ki). The CPI kinetics in the presence and absence of strong and weak OATP1B inhibitors (rifampin and GDC‐0810) were described well with a one‐compartment model, and in vivo Ki were estimated. Clinical DDIs between pravastatin and these inhibitors were predicted using physiologically based pharmacokinetic (PBPK) models coupled with the estimated in vivo Ki and predicted magnitude matched well with the observed DDIs. In conclusion, model‐based analysis of the CPI profile has the potential to quantitatively predict liability of a new molecular entity (NME) as an OATP1B inhibitor early in drug development.

Dose‐Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate Biomarkers and OATP1B Probe Drugs

“…However, attention should be paid to the substrate‐dependence that may impact the prediction of OATP1B‐mediated DDI with NCEs. Several groups, including ourselves, have proposed a model‐based approach as a way to translate the AUCR values obtained with endogenous compounds to DDI with drugs, such as statins, with correction for the substrate‐dependence in the in vitro K i . Therefore, it is envisioned that a cadre of three to four OATP1B biomarkers could be deployed in support of phase I (NCE ascending dose) studies to derive a range of K i,app values, as a signature, and then compare with the in vitro derived K i values.…”

“…ARTICLE substrate-dependence in the in vitro K i . 24,30,31 Therefore, it is envisioned that a cadre of three to four OATP1B biomarkers could be deployed in support of phase I (NCE ascending dose) studies to derive a range of K i,app values, as a signature, and then compare with the in vitro derived K i values. In turn, adjustment for substratedependent differences in the in vitro K i would support derivation of K i,app values for statin drugs as input for physiologically-based pharmacokinetic (PBPK) modeling.…”

PBPK Modeling of Coproporphyrin I as an Endogenous Biomarker for Drug Interactions Involving Inhibition of Hepatic OATP1B1 and OATP1B3

“…Yoshida et al . summarized the effects of Rotor Syndrome (RS) on the urinary excretion of CP‐I from six previous articles.…”

“…They showed the difference of in vivo RIF K i,u for the hepatic elimination of CP‐I (0.13 μM) and rosuvastatin (0.25 μM). Yoshida et al . have also adopted an empirical model for CP‐I.…”

“…Although MRP2 is also expressed on human kidney proximal tubule epithelia, 30 inhibition of renal MRP2 was not incorporated in our PBPK model because the renal clearance of CP-I is not affected by RIF. 12 Yoshida et al 31 summarized the effects of Rotor Syndrome (RS) on the urinary excretion of CP-I from six previous articles. It was concluded that the ratio of urinary excretion in healthy control (non-RS) subjects vs. patients with RS (non-RS/RS) was comparable across the various studies, ranging from 5-20% with the geometric mean of 9.8%.…”