Chronic Administration of Tenofovir to Rhesus Macaques from Infancy through Adulthood and Pregnancy: Summary of Pharmacokinetics and Biological and Virological Effects
- 1 September 2008
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 52 (9), 3144-3160
- https://doi.org/10.1128/aac.00350-08
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.Keywords
This publication has 66 references indexed in Scilit:
- Effect of tenofovir on renal glomerular and tubular functionAIDS, 2007
- Evidence and Possible Consequences of the Phosphorylation of Nucleoside Reverse Transcriptase Inhibitors in Human Red Blood CellsAntimicrobial Agents and Chemotherapy, 2007
- In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected childrenAIDS, 2007
- Sequential emergence and clinical implications of viral mutants with K70E and K65R mutation in reverse transcriptase during prolonged tenofovir monotherapy in rhesus macaques with chronic RT-SHIV infectionRetrovirology, 2007
- Mechanism of Active Renal Tubular Efflux of TenofovirAntimicrobial Agents and Chemotherapy, 2006
- Efficacy and Safety of Tenofovir DF vs Stavudine in Combination Therapy in Antiretroviral-Naive PatientsA 3-Year Randomized TrialPublished by American Medical Association (AMA) ,2004
- Biological Effects of Short-Term or Prolonged Administration of 9-[2-(Phosphonomethoxy)Propyl]Adenine (Tenofovir) to Newborn and Infant Rhesus MacaquesAntimicrobial Agents and Chemotherapy, 2004
- Tenofovir Disoproxil FumarateClinical Pharmacokinetics, 2004
- Clinical Pharmacokinetics of the Antiviral Nucleotide Analogues Cidofovir and AdefovirClinical Pharmacokinetics, 1999
- RENAL EXTRACTION OF PARA-AMINOHIPPURATE IN INFANTS AND CHILDREN*JCI Insight, 1963