Physiologically Based Pharmacokinetic Modelling with Dynamic PET Data to Study the In Vivo Effects of Transporter Inhibition on Hepatobiliary Clearance in Mice

摘要

Physiologically based pharmacokinetic modelling (PBPK) is a powerful tool to predict in vivo pharmacokinetics based on physiological parameters and data from in vivo studies and in vitro assays. In vivo PBPK modelling in laboratory animals by noninvasive imaging could help to improve the in vivo-in vivo translation towards human pharmacokinetics modelling. We evaluated the feasibility of PBPK modelling with PET data from mice. We used data from two of our PET tracers under development, [¹¹C]AM7 and [¹¹C]MT107. PET images suggested hepatobiliary excretion which was reduced after cyclosporine administration. We fitted the time-activity curves of blood, liver, gallbladder/intestine, kidney, and peripheral tissue to a compartment model and compared the resulting pharmacokinetic parameters under control conditions ([¹¹C]AM7 n = 2; [¹¹C]MT107, n = 4) and after administration of cyclosporine ([¹¹C]MT107, n = 4). The modelling revealed a significant reduction in [¹¹C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 μl/min after cyclosporine administration. The excretion profile of [¹¹C]MT107 was shifted from predominantly hepatobiliary (CLH/CLR = 3.8 ± 3.0) to equal hepatobiliary and renal clearance (CLH/CLR = 0.9 ± 0.2). Our results show the potential of PBPK modelling for characterizing the in vivo effects of transporter inhibition on whole-body and organ-specific pharmacokinetics.