Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): Safety and efficacy studies

9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) significantly inhibits vir al reverse transcription and has been reported to sustain low virus load in SIV-infected rhesus monkeys. Based on these findings, studies were conduct ed to assess the safety, efficacy, and placental transfer of PMPA when admi nistered once daily subcutaneously to gravid rhesus monkeys during the seco nd and third trimesters and their offspring (30 mg/kg/day). Fetuses (SIV-in fected, N = 6; noninfected, N = 6) were monitored sonographically, and mate rnal/fetal blood samples were collected at select time points for hematolog ic, clinical chemical, virologic, immunologic, and pharmacologic assessment s. Newborns were delivered by cesarean section at term and nursery reared f or postnatal studies. Infants were administered PMPA once daily beginning o n day 2 of life until 9 months postnatal age. Results of these studies have shown significant placental transport of PMPA, with peak fetal levels at 1 to 3 hours post-maternal administration; a significant and sustained reduc tion in viral load in SIV-infected fetuses and infants; and marked improvem ents in outcome (e.g., survival, growth, health) in SIV-infected offspring. However, decreased infant body weights and alterations of select serum bio chemical parameters (e.g., decreased phosphorus levels, elevated alkaline p hosphatase) have been shown to occur in similar to 67% of PMPA-treated infa nts, with severe growth restriction and bone-related toxicity in similar to 25% of animals studied. These data suggest that although PMPA holds great promise for HIV-infected patients, there is the potential for bone-related toxicity at chronic, high dosages, particularly in infants.