Improving Prediction of Metabolic Clearance Using Quantitative Extrapolation of Results Obtained From Human Hepatic Micropatterned Cocultures Model and by Considering the Impact of Albumin Binding

Abstract

The objective was to compare, with the same data set, the predictive performance of 3 in vitro assays of hepatic clearance (CL), namely, micropatterned cocultures (also referring to HepatoPac^®) and suspension as well as monolayer hepatocytes to define which assay is the most accurate. Furthermore, existing in vitro-to-in vivo extrapolation (IVIVE) methods were challenged to verify which method is the most predictive (i.e., direct scaling method without binding correction, conventional method based either on the unbound fraction in plasma (fu_p) according to the free-drug hypothesis, or based on an fu_p value adjusted for the albumin [ALB]-facilitated hepatic uptake phenomenon). Accordingly, the role of ALB binding was specifically challenged, and consequently, the ALB production was monitored in parallel to the metabolic stability. The ALB concentration data were used to compare the in vitro assays and to adjust the value of fu_p of each drug to mimic the ALB-facilitated hepatic uptake phenomenon. The results confirmed that the direct and conventional IVIVE methods generally overpredicted and underpredicted the CL in vivo in humans, respectively. However, the underprediction of the conventional IVIVE method based on fu_p was significantly reduced from data generated with the HepatoPac^® system compared with the 2 other in vitro assays, which is possibly because that system is producing ALB at a rate much closer to the in vivo condition in liver. Hence, these observations suggest that the presence of more ALB molecules per hepatocyte in that HepatoPac^® system may have facilitated the hepatic uptake of several bound drugs because their intrinsic CL was increased instead of being decreased by the ALB binding effect. Accordingly, the IVIVE method based on the fu_p value adjusted for the ALB-facilitated uptake phenomenon gave the lowest prediction bias from the statistical analyses. This study indicated that the HepatoPac^® system combined with the adjusted value of fu_p was the most reliable IVIVE method and revealed the importance of quantifying the in vitro-to-in vivo variation of ALB concentration to improve the CL predictions, which would help any future physiologically based pharmacokinetics modeling exercise.

Keywords: ADME; DMPK; IVIVC; hepatocytes; liver models; pharmacokinetics; physiologically-based pharmacokinetics.