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

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 afer cyclosporine administration. We ftted 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 afer administration of cyclosporine ([11C]MT107, n=4). Te modelling revealed a signifcant reduction in [11C]MT107 hepatobiliary clearance from 35.2 ± 10.9 to 17.1 ± 5.6 nl/min afer cyclosporine administration. Te excretion profle of [11C]MT107 was shifed 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 efects of transporter inhibition on whole-body and organ-specifc pharmacokinetics.