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Antimicrobial Agents and Chemotherapy, November 1998, p. 2804-2809, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Pharmacodynamics of (-)-beta -2',3'-Dideoxy-3'-Thiacytidine in Chronically Virus-Infected Woodchucks Compared to Its Pharmacodynamics in Humans

Selwyn J. Hurwitz,1 Bud C. Tennant,2 Brent E. Korba,3 John L. Gerin,3 and Raymond F. Schinazi1,*

Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine and Veterans Affairs Medical Center, Decatur, Georgia 300331; Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 148532; and Georgetown University, Division of Molecular Virology and Immunology, Rockville, Maryland 208523

Received 11 December 1997/Returned for modification 1 April 1998/Accepted 10 August 1998

The pharmacodynamics of (-)-beta -2',3'-dideoxy-3'-thiacytidine (3TC) was studied in chronically woodchuck hepatitis virus-infected woodchucks and compared to that in previous studies in hepatitis B virus (HBV)-infected humans. Net depletion rates of serum virus DNA in woodchucks receiving 3TC were modeled as a sum of an exponentially declining virus input and a first-order elimination. Preceding shoulders and pseudo-first-order virus half-lives in serum ranged from 1 to 7 days and were dose dependent. Higher plasma 3TC concentrations were needed in woodchucks for virus depletion similar to that attained in humans. Human HBV depletion curves from a previous clinical study with 3TC (>= 100 mg per day) were described by a biexponential relationship. The average half-life value in humans, normalized to fraction of area under the serum virus load-time curve, was similar to the average half-life value observed in woodchucks given the highest 3TC dose (2.4 and 2.0 days, respectively). On cessation of therapy, virus load rebounds in woodchucks were dose dependent and resembled posttherapy virus "flares" reported to occur in humans. The estimates of drug exposures that could lead to optimal antiviral effects presented indicate that 3TC should not be underdosed and compliance should be monitored. The study of chronically infected woodchucks may prove useful for optimizing drug regimens for hepadnavirus infections.

* 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.

Antimicrobial Agents and Chemotherapy, November 1998, p. 2804-2809, Vol. 42, No. 11
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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Copyright © 1998 by the American Society for Microbiology. All rights reserved.