February 14, 2023
SPOTLIGHT - Translatability of in vitro Inhibition Potency to in vivo P-Glycoprotein Mediated Drug Interaction Risk
This publication is a result of a collaboration of SOLVO R&D colleagues with Pfizer’s scientists. We are proud to contribute together to new scientific insights for the ADME/DMPK community!
Sarah Lazzaro, Mark A West, Soraya Eatemadpour, Bo Feng, Manthena V S Varma, A David Rodrigues, Csilla Temesszentandrási-Ambrus, Péter Kovács-Hajdu, Zsuzsanna Nerada, Zsuzsanna Gáborik, Chester Costales
In vitro investigation of the potential risk of transporter-mediated drug-drug interactions has been required by regulatory agencies such as the FDA and the EMA for all new drug filings. For conducting these tests, multiple assay types and formats are available, and the choice is ultimately left up to the sponsor.
How to make sure the chosen system is reliable, and the inhibition data will indeed accurately predict DDI risk?
Variability in inhibition IC50 values across systems and laboratories has been reported but until very recently, little information was available on the potential causes of these differences and their effect on DDI prediction. Our publication contributes to this a body of data on in vitro transporter assay performance that can guide system selection for DDI prediction studies.
For this paper, inhibition of the MDR1 (P-gp) efflux transporter was compared for 28 reference compounds across multiple calibrated assay systems independently in two labs in collaboration with Pfizer Inc. For each assay type, good concordance of IC50 values was found across laboratories which was the strongest for vesicle-based (VT) assays, while assay sensitivity and selectivity were similar. VT assays offer a simpler and higher throughput alternative to cell-based testing for DDI prediction. Interacting drug concentrations in the VT assay are more controllable as complex cellular mechanisms that affect intracellular drug levels are absent, and results are thus also less dependent on the nature of the inhibitor. The study also found MDR1 inhibition IC50 values to depend on transporter expression levels as well as potential substrate nature of drugs.
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