Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques

Koen K.A. Van Rompay, Laurie L. Brignolo, Dennis J. Meyer, Christopher Jerome, Ross Tarara, Abigail Spinner, Marta Hamilton, Linda L. Hirst, David R. Bennett, Don R. Canfield, Trish G. Dearman, Wilhelm Von Morgenland, Phil C. Allen, Celia Valverde, Alesha B. Castillo, R. Bruce Martin, Valerie F. Samii, Ray Bendele, John Desjardins, Marta L. MarthasNiels C. Pedersen, Norbert Bischofberger

    Research output: Contribution to journalArticle

    Abstract

    The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl] adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.

    Original languageEnglish (US)
    Pages (from-to)1469-1487
    Number of pages19
    JournalAntimicrobial agents and chemotherapy
    Volume48
    Issue number5
    DOIs
    StatePublished - May 1 2004

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    ASJC Scopus subject areas

    • Pharmacology
    • Pharmacology (medical)
    • Infectious Diseases

    Cite this

    Van Rompay, K. K. A., Brignolo, L. L., Meyer, D. J., Jerome, C., Tarara, R., Spinner, A., Hamilton, M., Hirst, L. L., Bennett, D. R., Canfield, D. R., Dearman, T. G., Von Morgenland, W., Allen, P. C., Valverde, C., Castillo, A. B., Martin, R. B., Samii, V. F., Bendele, R., Desjardins, J., ... Bischofberger, N. (2004). Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus Macaques. Antimicrobial agents and chemotherapy, 48(5), 1469-1487. https://doi.org/10.1128/AAC.48.5.1469-1487.2004