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Antimicrobial Agents and Chemotherapy, February 2005, p. 560-564, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.560-564.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Pharmacokinetics of the Antiviral Agent ß-L-3'-Fluoro-2',3'-Didehydro-2',3'-Dideoxycytidine in Rhesus Monkeys{dagger}

Ghazia Asif,1,2 Selwyn J. Hurwitz,1,2 Giuseppe Gumina,3 Chung K. Chu,3 Harold M. McClure,4 and Raymond F. Schinazi1,2,4*

Department of Pediatrics,1 Yerkes Regional Primate Research Center, Emory University, Atlanta,4 Veterans Affairs Medical Center, Decatur,2 College of Pharmacy, University of Georgia, Athens, Georgia3

Received 25 June 2004/ Returned for modification 10 September 2004/ Accepted 12 October 2004

ß-L-3'-Fluoro-2',3'-didehydro-2',3'-dideoxycytidine (L-3'-Fd4C) is a potent and selective antiretroviral nucleoside with activity against lamivudine-resistant human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV) in vitro. The pharmacokinetics of L-3'-Fd4C were characterized in three rhesus monkeys given single intravenous and oral doses. A two-compartment open model was fitted to the plasma and urine data. Plasma concentrations declined in a biexponential fashion with an average beta half-life of 12.45 h and central and steady-state volumes of distribution of 0.43 and 1.90 liters/kg, respectively. The average systemic and renal clearance values were 0.23 and 0.08 liters/kg, respectively, and the apparent mean terminal half-life of the oral dose was 12.5 h. The serum concentrations exceeded the 90% effective concentration value for lamivudine-resistant and wild-type HIV-1 after oral administrations. A large variation was observed in the oral bioavailability, which ranged from 15 to 31%. To determine whether the bioavailability may be improved by using a basic buffer solution, the oral dose was repeated to the same animals in a sodium bicarbonate solution. The bioavailability of L-3'-Fd4C administered with sodium bicarbonate was not significantly different from the bioavailability when the oral dose was administered in the absence of buffer (P = 0.49), suggesting that further development of this compound may warrant other approaches, such as development of a prodrug to improve its oral absorption.

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

{dagger} This paper is dedicated to our colleague Harold McClure (1937-2004).

Antimicrobial Agents and Chemotherapy, February 2005, p. 560-564, Vol. 49, No. 2
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.2.560-564.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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