Grizzle TB, Rousseau FS, Moxham CP, Szczech GM; Interscience Conference on Antimicrobial Agents and Chemotherapy.

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 1998 Sep 24-27; 38: 366 (abstract no. I-12).

Triangle Pharmaceuticals, Inc., Durham, NC.

MKC-442 is a potent NNRTI currently in Phase II/III pivotal clinical trials for treatment of HIV-1 infection in adults. In order to investigate the potential for reproductive and teratogenic effects, MKC-442 was orally administered to Sprague Dawley (CD) rats and New Zealand White rabbits. The following protocol designs were used: 1) rat fertility and early embryonic development to implantation (Seg I); 2) rat teratology study (Seg II); 3) rabbit teratology study (Seg II); and 4) rat peri/postnatal development (Seg III). In all the protocols, doses tested were 0, 10, 40, and 160 mg MKC-442/kg/day; a high dose that gave exposures approximately 8 times the human exposure based upon mg of MKC-442/kg/day, and 2.6 times the human exposure based upon AUCO-21 comparisons with the rat. MKC-442 had no effect on fertility, sperm count or motility, or early embryonic development in rats. There were no increases in fetal abnormalities in the rat and rabbit teratology studies. In the peri/postnatal development study (Seg-III), pregnant rats in the high-dose group and pups in the mid- and high-dose groups weighed less than controls, but pregnancy rates, live birth indices, and pup viability were normal for all groups. Developmental landmarks, behavioral tests, and reproductive capacity were normal for all groups. Toxicokinetic evaluations for the Seg II studies are in progress. It was concluded that there was no reproductive toxicity or teratogenicity associated with orally administered MKC-442. Taken together with demonstrated efficacy in adult patients, this makes MKC-442 an attractive candidate for clinical trials in the prevention of maternofetal transmission of HIV-1 and treatment of pediatric patients.

Publication Types:

• Meeting Abstracts

Keywords:

• 6-benzyl-1-(ethoxymethyl)-5-isopropyluracil
• Abnormalities, Drug-Induced
• Adult
• Animals
• Body Weight
• Child
• Female
• Fertility
• HIV-1
• Humans
• Live Birth
• Male
• Muridae
• Pregnancy
• Rabbits
• Rats
• Rats, Inbred Strains
• Rats, Sprague-Dawley
• Reverse Transcriptase Inhibitors
• Safety
• Teratology
• Uracil
• abnormalities
• reverse transcriptase, Human immunodeficiency virus 1

Other ID:

• 20710817

UI: 102188129

From Meeting Abstracts