Administration of 9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) to Gravid and Infant Rhesus Macaques (Macaca mulatta): Safety and Efficacy Studies

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Abstract
9-[2-(R)-(phosphonomethoxy)propyl]adenine (PMPA) significantly inhibits viral reverse transcription and has been reported to sustain low virus load in SIV-infected rhesus monkeys. Based on these findings, studies were conducted to assess the safety, efficacy, and placental transfer of PMPA when administered once daily subcutaneously to gravid rhesus monkeys during the second and third trimesters and their offspring (30 mg/kg/day). Fetuses (SIV-infected, N = 6; noninfected, N = 6) were monitored sonographically, and maternal/fetal blood samples were collected at select time points for hematologic, clinical chemical, virologic, immunologic, and pharmacologic assessments. Newborns were delivered by cesarean section at term and nursery reared for postnatal studies. Infants were administered PMPA once daily beginning on 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 reduction in viral load in SIV-infected fetuses and infants; and marked improvements in outcome (e.g., survival, growth, health) in SIV-infected offspring. However, decreased infant body weights and alterations of select serum biochemical parameters (e.g., decreased phosphorus levels, elevated alkaline phosphatase) have been shown to occur in ∼67% of PMPA-treated infants, with severe growth restriction and bone-related toxicity in ∼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.

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