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Antimicrobial Agents and Chemotherapy, July 2007, p. 2424-2429, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01498-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of the Anti-Human Immunodeficiency Virus Agent 1-(β-D-Dioxolane)Thymine in Rhesus Monkeys{triangledown} ,{dagger}

Ghazia Asif,1,3 Selwyn J. Hurwitz,1,3 Aleksandr Obikhod,1,3 David Delinsky,1,3 Janarthanan Narayanasamy,4 Chung K. Chu,4 Harold M. McClure,2 and Raymond F. Schinazi1,2,3*

Department of Pediatrics,1 Yerkes National Primate Research Center, Emory University School of Medicine, Atlanta, Georgia,2 Veterans Affairs Medical Center, Decatur, Georgia 30033,3 College of Pharmacy, University of Georgia, Athens, Georgia4

Received 28 November 2006/ Returned for modification 26 March 2007/ Accepted 30 April 2007

β-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.

* Corresponding author. Mailing address: Veterans Affairs Medical Center, Medical Research 151H, 1670 Clairmont Road, Decatur, GA 30033. Phone: (404) 728-7711. Fax: (404) 728-7726. E-mail: rschina{at}emory.edu

{triangledown} Published ahead of print on 7 May 2007.

{dagger} Dedicated to our friend and colleague, Harold M. McClure (1937-2004).

Antimicrobial Agents and Chemotherapy, July 2007, p. 2424-2429, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.01498-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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