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Antimicrobial Agents and Chemotherapy, May 2004, p. 1469-1487, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1469-1487.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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,1* Laurie L. Brignolo,1 Dennis J. Meyer,2,{dagger} Christopher Jerome,3 Ross Tarara,1 Abigail Spinner,1 Marta Hamilton,2,{ddagger} Linda L. Hirst,1 David R. Bennett,1 Don R. Canfield,1 Trish G. Dearman,1 Wilhelm Von Morgenland,1 Phil C. Allen,1 Celia Valverde,1 Alesha B. Castillo,4 R. Bruce Martin,4 Valerie F. Samii,5 Ray Bendele,2,{ddagger} John Desjardins,2,{ddagger} Marta L. Marthas,1 Niels C. Pedersen,6 and Norbert Bischofberger2

California National Primate Research Center,1 Orthopaedic Research Laboratories,4 Department of Veterinary Medicine & Epidemiology, University of California, Davis, California 95616,6 Gilead Sciences, Foster City, California 94404,2 SkeleTech, Inc., Bothell, Washington 98021,3 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, Columbus, Ohio 432105

Received 3 October 2003/ Returned for modification 13 November 2003/ Accepted 21 January 2004

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.

* Corresponding author. Mailing address: California National Primate Research Center, County Road 98 and Hutchison, University of California, Davis, Davis, CA 95616. Phone: (530) 752-5281. Fax: (530) 754-4411. E-mail: kkvanrompay{at}ucdavis.edu.

{dagger} Present address: Charles River Laboratories, Sparks, NV 89431.

{ddagger} Present address: OSI Pharmaceuticals, Boulder, CO 80301.

Antimicrobial Agents and Chemotherapy, May 2004, p. 1469-1487, Vol. 48, No. 5
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.5.1469-1487.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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