Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques.

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.

• Authors: 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 Marthas, Niels C Pedersen, Norbert Bischofberger
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 48 Issue 5 Pg. 1469-87 (May 2004) ISSN: 0066-4804 [Print] United States
• PMID: 15105094 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-HIV Agents
• Organophosphonates
• Organophosphorus Compounds
• Phosphorus
• Tenofovir
• Adenine

Topics

• Absorptiometry, Photon
• Adenine (administration & dosage, analogs & derivatives, pharmacokinetics, toxicity)
• Animals
• Animals, Newborn (physiology)
• Anti-HIV Agents (administration & dosage, pharmacokinetics, toxicity)
• Area Under Curve
• Blood Chemical Analysis
• Bone Density (drug effects)
• Bone and Bones (diagnostic imaging, drug effects, pathology)
• Dose-Response Relationship, Drug
• Fanconi Syndrome (chemically induced, physiopathology)
• Female
• Glycosuria (chemically induced, metabolism)
• Half-Life
• Macaca mulatta
• Male
• Organophosphonates
• Organophosphorus Compounds (administration & dosage, pharmacokinetics, toxicity)
• Phosphorus (urine)
• Tenofovir
• Time Factors
• Weight Gain (drug effects)