Effect of OATP1B1/1B3 Inhibitor GDC‐0810 on the Pharmacokinetics of Pravastatin and Coproporphyrin I/III in Healthy Female Subjects

Abstract

Developed as an oral anticancer drug to treat estrogen receptor-positive breast cancer, GDC-0810 was shown to be a potent inhibitor of organic anion-transporting polypeptide 1B1 and 1B3 (OATP1B1/1B3) from an in vitro assay. A clinical study was conducted to assess the drug-drug interaction potential between GDC-0810 and pravastatin, which is a relatively selective and sensitive OATP1B1/1B3 substrate. Fifteen healthy female subjects of non-childbearing potential were enrolled in the study. On day 1 in period 1, a single 10-mg dose of pravastatin was administered to all subjects. Following a 4-day washout period, 600 mg of GDC-0810 was administered once daily on days 5 through 8 in period 2 to achieve steady-state concentrations. On day 7, a single dose of 10-mg pravastatin was coadministered with the 600-mg GDC-0810 dose. Concentrations of pravastatin (periods 1 and 2) and GDC-0810 (period 2 only) were quantified in blood samples and subsequently used to calculate the pharmacokinetics (PK) parameters. The pravastatin mean maximal concentration and area under the curve values were approximately 20% and 41% higher, respectively, following pravastatin coadministration with GDC-0810 compared to pravastatin alone. Based on the magnitude of change in this drug-drug interaction study, dose adjustments for pravastatin (and other OATP1B1/1B3 substrates) were not considered necessary when administered with GDC-0810. Retrospectively, the endogenous biomarkers of OATP1B1/1B3, coproporphyrin I and III, were also measured and showed changes comparable to those of pravastatin, indicating their utility in detecting weak inhibition of OATP1B1/1B3 in the clinical setting.

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

“…However, quantitative extrapolation for accurate clinical DDIs remains challenging. In the current study, estimated in vivo K i,u from biomarker kinetic profiles (rifampin: 0.0203 μM; GDC‐0810: 0.00174 μM; Table ) were much smaller than reported in vitro K i, (rifampin: ∼2 μM, GDC‐0810: 0.9 μM for OATP1B3 and ∼80% inhibition at 0.3 μM for OATP1B1), which were consistent with the above‐mentioned retrospective analyses. Indeed, these in vivo K i,u resulted in accurate prediction of clinical DDIs ( Figure ).…”

“…However, the plasma concentration of rifampin measured in the study evaluating the interaction between CPI and rifampin had twofold higher C max and a longer terminal half‐life. Preliminary analysis of CPI data with an updated rifampin model that matched observed time‐profile in another paper resulted in estimated K i,u,RIF of 0.13 μM, which was approximately five‐times higher than the estimated value using the default rifampin model (results not shown). These observations highlight the importance of carefully choosing the inhibitor models and using the same model of inhibitors for parameter estimation with CPI and DDI predictions with probe substrates, as the use of different PBPK models can cause discrepancies in the predicted magnitude of inhibition.…”

“…Plasma concentration‐time profiles of CPI in the presence of rifampin or GDC‐0810 were used for model‐based analysis. General workflow of the model‐based analysis of CPI kinetics and the prediction of clinical DDIs is described in Figure .…”

“…For GDC‐0810, K i,u values were increased/decreased by threefold, as there were little variation in the estimated K i,u values in the above sensitivity analysis. The simulated AUC ratios (AUCRs) were compared with reported AUCR in clinical DDI studies …”

“…first demonstrated that CPI and CPIII showed comparable levels of increases in exposures as that of rosuvastatin, an OATP1B probe substrate, in the presence of OATP1B inhibitor rifampin in humans. Liu et al . later demonstrated that these biomarkers are also sensitive to detect weak inhibition of OATP1B by GDC‐0810, an orally bioavailable selective estrogen receptor downregulator, suggesting CPI and CPIII as promising alternatives to probe substrates in evaluating OATP1B‐mediated DDIs.…”