Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for Treatment of Hepatitis

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http://aac.asm.org/cgi/content/abstract/52/7/2521

Antimicrobial Agents and Chemotherapy, July 2008, p. 2521-2528, Vol. 52, No. 7

0066-4804/08/$08.00+0 doi:10.1128/AAC.00029-08

Nonclinical Safety Profile of Telbivudine, a Novel Potent Antiviral Agent for

Treatment of Hepatitis B

G. Bridges, Jules R. Selden,* and Shouqi Luo

Idenix Pharmaceuticals, Inc., One Kendall Square, Cambridge, Massachusetts 02139

Received 8 January 2008/ Returned for modification 11 February 2008/ Accepted 4

May 2008

Telbivudine is a novel nucleoside drug recently approved for the treatment of

patients with chronic hepatitis B. Its nonclinical safety was evaluated in a

comprehensive program of studies, including safety pharmacology, acute and

chronic toxicity, reproductive and developmental toxicity, genotoxicity, and

carcinogenicity. There were no test article-related effects observed in an in

vitro hERG assay or in a core battery of safety pharmacology studies (central

nervous system, respiratory, and cardiovascular safety pharmacology studies).

Telbivudine was well tolerated in rats and in monkeys following single oral

doses up to 2,000 mg/kg/day. Except for equivocal axonopathic findings in

monkeys and occasional incidences of emesis, soft feces, and minor changes in

body weight and food consumption, there was no target organ toxicity observed in

mice, rats, or monkeys following oral administration for up to 3, 6, or 9

months, respectively, at doses up to 3,000 mg/kg/day. Axonopathy in the sciatic

nerves and in the spinal cords of monkeys dosed at 1,000 mg/kg/day observed in a

9-month study was considered equivocal, as the role of telbivudine in the injury

could not be determined. Slightly higher incidences of abortion and premature

delivery observed in rabbits dosed at 1,000 mg/kg/day were considered secondary

to maternal toxicity. There was no evidence of genotoxicity or carcinogenicity.

These results suggest that telbivudine has a favorable safety profile and

support its use in patients with chronic compensated hepatitis B viral

infection.

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* Corresponding author. Mailing address: Idenix Pharmaceuticals, Inc., 60

Hampshire Street, Cambridge, MA 02139. Phone: (617) 995-9800. Fax: (617)

224-4350. E-mail: selden.jules@...

Published ahead of print on 12 May 2008.

Present address: West Virginia School of Osteopathic Medicine, 400 North Lee

Street, burg, WV 24901.

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Antimicrobial Agents and Chemotherapy, July 2008, p. 2521-2528, Vol. 52, No. 7

0066-4804/08/$08.00+0 doi:10.1128/AAC.00029-08

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