E-002 - REDUCTION IN ESTIMATED GLOMERULAR FILTRATION RATE (EGFR) OBSERVED WITH DORAVIRINE (DOR) IS CAUSED BY INHIBITION OF ORGANIC CATION TRANSPORTER 2 (OCT2)

Y. Li¹, X. Chu², R. Sanchez¹, R. Carstens³, M. Pisculli³, S. Klopfer⁴, Z. Xu⁴, R. Lahoulou⁵, R. Plank³; ¹Merck & Co., Inc., Pharmacokinetics, Merck & Co., Inc., Rahway, NJ, USA, ²Merck & Co., Inc., West Point, PA, USA, ³Merck & Co., Inc., Clinical Research, Merck & Co., Inc., Rahway, NJ, USA, ⁴Merck & Co., Inc., Biostatistics, Merck & Co., Inc., Rahway, NJ, USA, ⁵MSD France, MSD France, Puteaux, France.

Background: In three Phase 3 studies of DOR in treatment-naïve adults with HIV-1, declines in creatinine-based eGFR of ~10 mL/min/1.73 m2 were observed within a few weeks of initiating DOR, regardless of concomitant tenofovir use, followed by stable eGFR for up to 3.5 years [1,2]. To assess the possible involvement of renal transporters, we investigated the in vitro interaction of DOR with OCT2 and with multidrug and toxin extrusion protein 1 (MATE1), which are responsible for active renal transport of creatinine.

Methods: In vitro inhibition assays were established in OCT2- and MATE1-transfected cells using [14C]-creatinine and metformin as probes. The inhibitory effects of DOR on OCT2- and MATE1-mediated uptake of creatinine and metformin were measured, and the FDA drug interaction risk assessment criteria were applied.

Results: Creatinine exhibited uptake ratios of 8- and 5-fold in OCT2- and MATE1-transfected cells, respectively, compared to parental cells. DOR inhibited OCT2-mediated creatinine uptake (Figure 1A) with an IC50 of 6.9 µM (~12-fold above DOR unbound Cmax), suggesting that eGFR reduction observed after initiation of DOR may be associated with inhibition of OCT2. When metformin was used as the OCT2 probe, a 10-fold higher IC50 for OCT2 inhibition was observed for DOR (67 µM). As previously demonstrated, DOR does not affect the pharmacokinetics of metformin [3], suggesting that DOR inhibition of OCT2 is substrate dependent. Finally, DOR inhibited ~48% of MATE1-mediated creatinine uptake at 100 µM, which is comparable to the inhibition potency for metformin uptake (Figure 1B).

Conclusion: At clinically relevant exposures, DOR inhibits OCT2- but not MATE1-mediated creatinine transport. Our in vitro observations mechanistically illustrate that the reduction in creatinine-based eGFR calculations observed with DOR is caused by inhibition of renal creatinine transport by DOR and does not reflect a reduction in renal function. These findings are consistent with clinical data showing improvement in eGFR, when calculated using cystatin-C, in treatment-naïve individuals initiating treatment with the DOR/islatravir combination [2]. Inhibition of renal creatinine transporters has been seen with other drugs, including antiretrovirals, and such effects are reversible with removal of the drug [4].