Reduction in estimated glomerular filtration rate observed with doravirine is caused by inhibition of organic cation transporter 2

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Doravirine (DOR), a potent nonnucleoside reverse transcriptase inhibitor for HIV-1 treatment, is primarily metabolized by cytochrome P450 3A enzymes to form doravirine carboxylic acid metabolite (M9), the major plasma metabolite excreted in urine. To investigate the estimated glomerular filtration rate decrease observed in phase 3 DOR studies, we investigated DOR and M9 interactions with renal transporters organic cation transporter 2 (OCT2), organic anion transporter 2 (OAT2), and multidrug and toxin extrusion proteins 1 and 2K (MATE1 and MATE2K). In vitro assays were conducted in OCT2- and OAT2-transfected human embryonic kidney 293 (HEK293) cells and MATE1- and MATE2K-transfected Madin-Darby canine kidney II cells. The inhibitory potency (half-maximal inhibitory concentration [IC 50 ]) of DOR and M9 on OCT2-, OAT2-, MATE1-, and MATE2K-mediated uptake of creatinine or metformin were measured, whereas substrate-dependent inhibition was assessed for OCT2 and MATE1. DOR inhibited OCT2-mediated creatinine uptake with an IC 50 of 6.9 ± 0.8 μ M, approximately 6.2-fold lower than that observed using metformin as probe. DOR also inhibited OAT2 at concentrations higher than clinically relevant (IC 50 of 28.7 ± 4.9 μ M). DOR did not inhibit MATE1-mediated creatinine uptake (IC 50 >100 μ M). M9, at concentrations higher than clinically relevant, inhibited OAT2-mediated creatinine uptake (IC 50 of 18.0 ± 2.1) but did not inhibit creatinine or metformin uptake by OCT2, MATE1, or MATE2K (IC 50 >30 μM for all). In conclusion, at clinically relevant exposures, DOR exhibited substrate-dependent inhibition of creatinine transport via OCT2, which could explain the slight decrease in calculated estimated glomerular filtration rate observed with DOR treatments, without reduction in renal function. Significance Statement At clinically relevant concentrations, doravirine inhibits the renal transporter organic cation transporter 2 in a substrate-dependent manner, but not organic anion transporter 2, multidrug and toxin extrusion proteins 1 and 2K, indicating that doravirine-associated estimated glomerular filtration rate reductions are caused by inhibition of renal creatinine transport and do not reflect a reduction in renal function.