Kunze, Annett. Prediction of human drug clearance and anticipation of clinical drug-drug interaction potential from in vitro drug transport studies. 2014, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_11053
To date, only few IVIVE approaches have been described to predict the human renal organ clearance based on filtration, secretion, and reabsorption. In a first study, we measured in LLC-PK1 cells the transport of 20 compounds with various physiochemical and PK properties. These data were incorporated into a novel kidney model to predict all renal clearance processes in human. Compared to reported renal clearances from clinical studies, the prediction accuracy in terms of percentage within three-fold error was 95%. Moreover, our model allowed the assessment of the contribution of filtration, secretion, and reabsorption to the net renal organ clearance in human.
In a second study, we investigated the contribution of the organic anion transporting polypeptides (OATP) 1 and OATP1B3 to the net hepatic uptake clearance of statins. For this purpose, the absolute transporter protein abundances were determined by liquid chromatography-tandem mass spectrometry in cryopreserved human hepatocytes and single-transporter expressing HEK293 cells. Subsequently, uptake kinetics of eight statins and OATP1B1 and OATP1B3-specific reference substrates were determined in all expression systems. Transporter activity data generated in recombinant cell lines were extrapolated to hepatocyte values using relative transporter expression factors (REF) or relative activity factors (RAF). We showed that REF and RAF-based predictions were highly similar indicating a direct transporter expression-activity relationship. Moreover, we demonstrated that the REF-scaling method provided a powerful tool to quantitatively assess the transporter-specific contributions to the net uptake clearance of statins in hepatocytes.
In a third study, we applied a recently developed IVIVE method to predict the human hepatic clearance and the DDI potential of eight statins. Application of the recently established Extended Clearance Concept Classification System (ECCCS), demonstrated a good predictability of the human hepatic clearance with six out of eight statins projected within a two-fold deviation to reported values. Furthermore, the DDI potential of the statins was assessed with respect to the impact of possible perpetrator drugs on hepatic uptake, metabolism, and biliary secretion and subsequently compared with reported clinical DDI effects. The predicted DDIs for statins showed excellent quantitative correlations with clinical observations. The ECCCS thus represents a powerful tool to anticipate the DDI potential of victim drugs based on in vitro drug metabolism and transport data.
In a last study, we assessed the inhibitory potential of telaprevir, a new, direct-acting antiviral drug, on major human renal and hepatic drug transporters. By that, co-incubations of drug-transporter reference substrates and telaprevir in stable, single-transporter transfected HEK293 cells was investigated. Our data showed that telaprevir exhibited significant potential to inhibit major renal and hepatic drug transporters in human. Therefore, clinical co-administration of telaprevir together with drugs that are substrates of renal and hepatic transporters should be carefully monitored.
Taken together, with the help of this work the safety profiles of NMEs can now be assessed in preclinical drug development based on in vitro methods. It is therefore expected, that the establishment, validation, and application of novel in vitro based methods, described in this work, will add significant value in the early assessment of the PK profile of NMEs.
|Committee Members:||Camenisch, Gian and Meyer zu Schwabedissen, Henriette E.|
|Faculties and Departments:||05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||114 S.|
|Last Modified:||30 Jun 2016 10:56|
|Deposited On:||23 Dec 2014 13:17|
Repository Staff Only: item control page