LB-014 - EXTRAPOLATING TRANSPORTER-MEDIATED DRUG-DRUG INTERACTION BETWEEN REMDESIVIR AND CLOFAZIMINE FROM IN VITRO TO IN VIVO: A STATIC APPROACH

M. Jony¹, S. Howlader¹, Y. Cho², D. Kim¹, J. Shin²; ¹Inje University, College of Medicine, Inje University, College of Medicine, Busan, South Korea, ²Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, , .

Background: In a recent study, the addition of 1.25 μM clofazimine (CFZ) in an in vitro assay resulted in a nearly 20-fold increase in the activity of remdesivir (RDV). Co-treatment with CFZ exhibited potent synergy, leading to reduced lung viral load and suppressed virus shedding in nasal wash samples, surpassing the effects achieved by individual treatments with RDV or CFZ alone. Additionally, the concentration-dependent activity of RDV against SARS-CoV-2 has been observed. Transporters may play a significant role in this phenomenon, as the intracellular exposure of RDV in the lungs, crucial for its in vivo antiviral activity against SARS-CoV-2, is influenced by activating enzymes, cellular uptake, and efflux transporters. We hypothesize that CFZ may enhance intracellular RDV concentrations by inhibiting efflux transporters, as CFZ is known to be a potential inhibitor of P-gp, BCRP, and MRPs. Therefore, this study evaluated the transporter-mediated drug-drug interaction (DDI) between RDV and CFZ in vitro.

Methods: An in vitro transporter assay was conducted using different cell lines stably overexpressed with ABC efflux and SLC uptake membrane transporters. The drug-drug interaction transport assay was carried out in the absence or presence of CFZ in a concentration-gradient manner. The concentration within the cell was then quantified by using tandem mass spectrometry (LC-MS/MS). The inhibition kinetic parameters were estimated using a nonlinear regression model. Then we used the in vitro data to predict the clinical DDI potential between CFZ and RDV using static approaches.

Results: RDV was found as a substrate of OATP1B1, P-gp, MRP1, and MRP2 with an intrinsic clearance (Clint) of 17.08 ± 7.7, 6.49 ± 0.61, 2.41 ± 0.34, and 25.02 ± 5.92 µL/min/mg protein, respectively. CFZ inhibited the P-gp, MRP1, and MRP2-mediated efflux of RDV with Ki values of 0.91 µM, 0.39 µM, and 17.17 µM, respectively. According to the static model, CFZ was predicted to potentially lead to clinically significant DDI mediated by P-gp (R = 0.45) and MRP1 (R = 1.05) with RDV, but not through MRP2 (R = 0.02).

Conclusion: RDV was found as a substrate of OATP1B1, P-gp, MRP1, and MRP2. CFZ inhibited the P-gp, MRP1, and MRP2-mediated efflux of RDV. According to the static model, CFZ was predicted to cause clinically significant DDI with RDV via P-gp and the MRP1 transporter.