Safety assessment, in vitro and in vivo, and pharmacokinetics of emivirine, a potent and selective nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5- isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor tha t displays potent and selective anti-human immunodeficiency virus type 1 (H IV-1) activity in vivo. EMV showed little or no toxicity towards human mito chondria or human bone marrow progenitor cells. Pharmacokinetics were linea r for both rats and monkeys, and oral absorption was 68% in rats. Whole-bod y autoradiography showed widespread distribution in tissue 30 min after rat s were given an oral dose of [C-14] EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the pla sma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolg us monkeys), toxicity was limited to readily reversible effects on the kidn ey consisting of vacuolation of kidney tubular epithelial cells and mild in creases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metaboliz ing enzymes. EMV tested negative for genotoxic activity, and except for dec reased feed consumption at the high dose (160 mg/kg/day), with resultant de creases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on ra ts and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.