In Vitro Pharmacokinetic Properties of MK-2048, a Potent Drug Candidate for HIV Prevention

MK-2048 is a potent second-generation HIV integrase inhibitor that has demonstrated acceptable safety and pharmacokinetics (PKs) in clinical trials of vaginal formulations. The substrate-type interactions between MK-2048 and the transporters/metabolizing enzymes that are highly expressed in the human female reproductive tract (FRT) were evaluated. The interactions between MK-2048 and P-gp/BCRP were investigated using a cellular bidirectional permeability assay, while those between MK-2048 and MRP4 were assessed using a vesicular uptake assay. Reaction phenotyping was performed to characterize the interactions between MK-2048 and CYP1A1 and CYP1B1. Using human cervicovaginal fluids (CVFs), MK-2048’s solubility was determined using a thermodynamic solubility method and its protein binding was determined using a rapid equilibrium dialysis method. Our study shows an efflux of MK-2048 in P-gp/BCRP-overexpressing MDCKII cells, which was reduced by a P-gp/BCRP inhibitor. Uptake of MK-2048 in MRP4/control vesicles was found to be ATP-independent. MK-2048 was metabolized by the CYP1A1 enzyme but not by CYP1B1. These data confirm that MK-2048 is a substrate of P-gp, BCRP, and CYP1A1, but is not a substrate of MRP4 or CYP1B1. MK-2048 displays low solubility and high protein binding in human CVF. This data suggests that MK-2048 may potentially interact with drugs that modulate the activity of P-gp, BCRP, and CYP1A1.