Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy

Summary of pharmacokinetics and biological and virological effects

Koen K.A. Van Rompay, Lucie Durand-Gasselin, Laurie L. Brignolo, Adrian S. Ray, Kristina Abel, Tomas Cihlar, Abigail Spinner, Christopher Jerome, Joseph Moore, Brian P. Kearney, Marta Marthas, Hans Reiser, Norbert Bischofberger

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

The reverse transcriptase (RT) inhibitor tenofovir (TFV) is highly effective in the simian immunodeficiency virus (SIV) macaque model of human immunodeficiency virus infection. The current report describes extended safety and efficacy data on 32 animals that received prolonged (≥1- to 13-year) daily subcutaneous TFV regimens. The likelihood of renal toxicity (proximal renal tubular dysfunction [PRTD]) correlated with plasma drug concentrations, which depended on the dosage regimen and age-related changes in drug clearance. Below a threshold area under the concentration-time curve for TFV in plasma of ∼10 μg·h/ml, an exposure severalfold higher than that observed in humans treated orally with 300 mg TFV disoproxil fumarate (TDF), prolonged TFV administration was not associated with PRTD based on urinalysis, serum chemistry analyses, bone mineral density, and clinical observations. At low-dose maintenance regimens, plasma TFV concentrations and intracellular TFV diphosphate concentrations were similar to or slightly higher than those observed in TDF-treated humans. No new toxicities were identified. The available evidence does not suggest teratogenic effects of prolonged low-dose TFV treatment; by the age of 10 years, one macaque, on TFV treatment since birth, had produced three offspring that were healthy by all criteria up to the age of 5 years. Despite the presence of viral variants with a lysine-to-arginine substitution at codon 65 (K65R) of RT in all 28 SIV-infected animals, 6 animals suppressed viremia to undetectable levels for as long as 12 years of TFV monotherapy. In conclusion, these findings illustrate the safety and sustained benefits of prolonged TFV-containing regimens throughout development from infancy to adulthood, including pregnancy.

Original languageEnglish (US)
Pages (from-to)3144-3160
Number of pages17
JournalAntimicrobial Agents and Chemotherapy
Volume52
Issue number9
DOIs
StatePublished - Sep 1 2008

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Tenofovir
Macaca mulatta
Pharmacokinetics
Pregnancy
Fanconi Syndrome
Simian Immunodeficiency Virus
Macaca
Safety
Fumarates
Reverse Transcriptase Inhibitors
Urinalysis

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy : Summary of pharmacokinetics and biological and virological effects. / Van Rompay, Koen K.A.; Durand-Gasselin, Lucie; Brignolo, Laurie L.; Ray, Adrian S.; Abel, Kristina; Cihlar, Tomas; Spinner, Abigail; Jerome, Christopher; Moore, Joseph; Kearney, Brian P.; Marthas, Marta; Reiser, Hans; Bischofberger, Norbert.

In: Antimicrobial Agents and Chemotherapy, Vol. 52, No. 9, 01.09.2008, p. 3144-3160.

Research output: Contribution to journalArticle

Van Rompay, KKA, Durand-Gasselin, L, Brignolo, LL, Ray, AS, Abel, K, Cihlar, T, Spinner, A, Jerome, C, Moore, J, Kearney, BP, Marthas, M, Reiser, H & Bischofberger, N 2008, 'Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: Summary of pharmacokinetics and biological and virological effects', Antimicrobial Agents and Chemotherapy, vol. 52, no. 9, pp. 3144-3160. https://doi.org/10.1128/AAC.00350-08
Van Rompay, Koen K.A. ; Durand-Gasselin, Lucie ; Brignolo, Laurie L. ; Ray, Adrian S. ; Abel, Kristina ; Cihlar, Tomas ; Spinner, Abigail ; Jerome, Christopher ; Moore, Joseph ; Kearney, Brian P. ; Marthas, Marta ; Reiser, Hans ; Bischofberger, Norbert. / Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy : Summary of pharmacokinetics and biological and virological effects. In: Antimicrobial Agents and Chemotherapy. 2008 ; Vol. 52, No. 9. pp. 3144-3160.
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