Pharmacokinetics of the anti-human immunodeficiency virus agent 1-(beta-D-dioxolane)thymine in rhesus monkeys.

Abstract

Beta-D-dioxolane-thymine (D-DOT) has potent and selective in vitro activity against several clinically important resistant human immunodeficiency virus (HIV) mutants and is in advanced preclinical development. Therefore, the single-dose intravenous and oral pharmacokinetics of D-DOT were studied with three rhesus monkeys. The pharmacokinetic profiles of D-DOT in serum and urine were adequately described by a two-compartment open pharmacokinetic model. D-DOT was rapidly and almost completely absorbed (absorption rate constant = 2.7 h(-1); fraction of oral dose absorbed = 0.82 to 1.06). The average serum beta half-life was 2.16 h. The average central and steady-state volumes of distributions were 0.52 and 1.02 liter/kg of body weight, respectively, and the average systemic and renal clearance values were 0.36 liter/h/kg and 0.18 liter/h/kg. Four or eight percent of administered D-DOT was eliminated in the urine as glucuronide within 8 h after intravenous or oral administration, respectively. D-DOT reached levels in the cerebrospinal fluid in excess of 10 to 20 times the median effective concentration for wild-type HIV and resistant mutants. The potent antiretroviral activity of D-DOT against a lamivudine- and zidovudine-resistant HIV-1 mutant, together with an excellent pharmacokinetic profile for rhesus monkeys, suggest that further development is warranted.

• Authors: Ghazia Asif, Selwyn J Hurwitz, Aleksandr Obikhod, David Delinsky, Janarthanan Narayanasamy, Chung K Chu, Harold M McClure, Raymond F Schinazi
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 51 Issue 7 Pg. 2424-9 (Jul 2007) ISSN: 0066-4804 [Print] United States
• PMID: 17485498 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antiviral Agents
• Dioxolanes
• dioxolane-thymine
• Thymine

Topics

• Administration, Oral
• Animals
• Antiviral Agents (administration & dosage, blood, cerebrospinal fluid, chemistry, pharmacokinetics, urine)
• Area Under Curve
• Calibration
• Chromatography, High Pressure Liquid
• Dioxolanes (administration & dosage, chemistry, pharmacokinetics)
• Female
• HIV-1
• Half-Life
• Injections, Intravenous
• Macaca mulatta
• Mass Spectrometry
• Metabolic Clearance Rate
• Molecular Structure
• Reference Standards
• Reproducibility of Results
• Thymine (administration & dosage, analogs & derivatives, chemistry, pharmacokinetics)