Maja Leimar (1), Linda Andersson (2), Yasunori Aoki (2) and Pär Nordell (2)
(1) (1) University of Gothenburg , Sweden (2) Astra Zeneca, Sweden
Objectives: In vitro systems are widely used in drug discovery to predict in vivo properties such as drug clearance, reducing the need of animal studies and increasing throughput. However, in cases where the activity in in vitro systems do not directly translate to the in vivo setting, such predictions can come with significant challenges. A mechanism that strongly can influence drug disposition is active uptake into the liver mediated by transporters like the organic anion transporting polypeptides (OATPs). OATPs are expressed at the basolateral membrane of hepatocytes facing the portal blood from where endogenous compounds as well as exogenous drugs are transported into the liver [1]. The latter includes statins which is a widely prescribed class of drugs identified as substrates of OATPs. As a consequence, the pharmacokinetics of some statins display significant sensitivity to OATP genetic variants and to co-administration of OATP inhibitors such as rifampicin. While cellular in vitro systems are widely used to study transporter kinetics, quantitative in vivo scaling remains challenging resulting in uncertainties in e.g. clearance predictions. We have here generated pre-clinical in vivo and in vitro data for a set of OATP substrates, and evaluated physiologically based pharmacokinetic modelling (PBPK) as a tool to quantitatively bridge the two settings.
Methods: In vivo pharmacokinetic plasma profiles in male Han Wistar rats of five known OATP substrates (valsartan, bosentan, telmisartan, pitavastatin and repaglinide) after iv administration at 1 mg/kg with and without oral co-administration of OATP inhibitor rifampicin at 30 mg/kg were generated, and liver exposure at termination was measured. Uptake kinetics in freshly isolated rat hepatocytes in suspension with and without inhibitor rifampicin was in parallel characterized for the same substrates in vitro using an oil-spin method [2]. A customised PBPK model [3] composed of 14 compartments was developed and implemented in R. To describe uptake to and elimination from the liver compartments, mechanisms for active uptake, passive diffusion and hepatic intrinsic clearance were incorporated. Model parameters based on a top-down approach were estimated by fitting in vivo data using the Cluster Gauss-Newton method [4] and the correlation to estimates scaled according to bottom-up principles from the in vitro system was investigated.
Results: All test compounds displayed significantly increased AUC in rats with co-administration of rifampicin (1.8 to 9.2-fold). The hepatocyte uptake was similarly reduced in vitro upon co-incubation with inhibitor (by 3 to 12-fold), reflecting the contribution of OATP-mediated cellular uptake. The PBPK model optimized based on a top-down approach could closely describe the observed in vivo data, and uptake parameters were estimated with acceptable precision. The correlation to corresponding uptake parameter values based on the in vitro model displayed significant residual variability, and a uniform scaling factor could not be confidently identified. A bottom-up PBPK modelling approach could however predict the AUC ratio upon inhibition of OATP transporters well: simulations for all five compounds were within 2-fold of the observations (AAFE = 1.7).
Conclusions: Comparison of predictions and observations showed that the relative impact of active uptake can be well translated from in vitro to in vivo using a PBPK modelling approach. The analysis additionally showed that challenges remain in predicting absolute pharmacokinetic profiles based solely on bottom-up principles, identifying tissue partitioning models as a limiting factor.
References:
[1] Giacomini KM. et al. Nat Rev Drug Discov. (2010) 9, 215-36.
[2] Nordell P. et al. Mol Pharm. (2013) 10, 4443-51.
[3] Sato M. et al. Drug Metab Dispos. (2018) 46, 740-8.
[4] Aoki Y. et al. Optim Eng (2022) 23, 169–99.
Reference: PAGE 32 (2024) Abstr 11209 [www.page-meeting.org/?abstract=11209]
Poster: Drug/Disease Modelling - Absorption & PBPK