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

Abstract

Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [ 14 C]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 plasma 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 cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.

Three-Drug Combinations of Emivirine and Nucleoside Reverse Transcriptase Inhibitors in Vitro: Long-Term Culture of HIV-1-Infected Cells and Breakthrough Viruses

“…EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. In addition, EMV has a favourable pharmacokinetic profile and good oral bioavailability (Szczech et al, 2000). These results supported the clinical efficacy studies with HIV-1-infected patients.…”

“…EMV is currently undergoing Phase III clinical trials to assess its efficacy in the treatment of HIV-1 infection in adults and children. EMV displays a favourable pharmacokinetic profile and good oral bioavailability (Szczech et al, 2000). Accordingly, the clinical trials have shown that EMV in combination with NRTIs has high antiviral activity, safety and tolerability in HIV-1-infected patients.…”

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

“…Further lead optimization led to the identification of MKC-442 (emivirine) (125) as the clinical drug candidate, but Mitsubishi Kasei Corporation (MKC), the owners of the compound, were concerned about possible drug resistance development. By the time this concern was alleviated (the compound was in the meantime transferred from MKC to Triangle Pharmaceuticals) (126), the landscape, with three NNRTIs on the market (nevirapine, delavirdine, and efavirenz), had become too competitive, and further development of emivirine was stopped. …”

Synthesis and anti‐HIV‐1 and anti‐HCMV Activity of 1‐Substituted 3‐(3,5‐Dimethylbenzyl)uracil Derivatives.

“…One compound of this type is 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) 6) and emivirine has entered clinical phase III trials. 7) Recently, Buckheit et al reported a unique and highly potent uracil derivative, 1-(3-cyclopenten-1-yl)methyl-6-(3,5-dimethylbenzoyl)-5-ethyl-2,4-pyrimidinedione (SJ-3366), which showed antiviral activity against HIV-2 as well as HIV-1. 8) Thereafter, many pyrimidine derivatives emerged as anti-HIV agents.…”

“…Therefore, the substituent at the N-3 position of uracil was fixed to the 3,5-dimethylbenzyl group. At first, the ethoxymethyl derivative (5b) was prepared resembling emivirine 7) . Allyl (5a) and 2-(methylthio)ethyl (5c) group were also introduced to N1 of 3b as non-cyclic substituents.…”