Background
Organic anion transporting polypeptides (OATPs) play a critical role in hepatic drug uptake and elimination. GDC-X inhibits OATP1B in vitro, raising the risk of clinical DDIs with OATP1B substrates. Coproporphyrin I (CPI) is an endogenous biomarker for OATP1B. This analysis aimed to predict the magnitude of clinical DDIs between GDC-X and rosuvastatin (an OATP1B probe substrate) using a CPI-informed modelling approach.
Methods
Data was obtained from a study with four dose groups (200 mg, 400 mg, 800 mg, and 1200 mg) of GDC-X. CPI data were utilised to estimate the in vivo Ki of GDC-X against OATP1Bs using NONMEM, incorporating previously predicted portal vein concentrations of GDC-X from Simcyp. Visual predictive checks and goodness-of-fit plots were generated. The estimated Ki value was incorporated into a previously developed PBPK model in Simcyp to predict the DDI between GDC-X and Rosuvastatin.
Results
At the steady-state concentration of GDC-X, CPI concentrations increased across all dose groups compared to pre-dose level. The mean CPI concentration in plasma increased from 0.79 (±0.23) ng/ml at baseline to 1.47 ± 0.16 ng/mL at steady state. The in vivo unbound Ki, OATP1B for GDC-X was about 0.188 µM, approximately fivefold lower than the in vitro (1.05 µM). The predicted CPI concentrations matched the observed concentrations. The predicted CPI Cmax ratio and rosuvastatin AUCR at 1200mg were: 1.8 and 1.5, respectively. Rosuvastatin AUCR increased with the dose. No significant DDI at 200 mg and a weak interaction (AUCR <2) was observed at the other doses.
Conclusion
The one-compartment model combined with Simcyp-predicted GDC-X pharmacokinetic profile described the observed plasma CPI concentrations. The predicted clinical DDI between GDC-X and Rosuvastatin was weak, with AUCR remaining below 2, indicating limited clinical significance.
