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Antimicrobial Agents and Chemotherapy, December 1998, p. 3218-3224, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease

Hing L. Sham,1,* Dale J. Kempf,1 Akhteruzammen Molla,1 Kennan C. Marsh,2 Gondi N. Kumar,3 Chih-Ming Chen,1 Warren Kati,1 Kent Stewart,4 Ritu Lal,5 Ann Hsu,5 David Betebenner,1 Marina Korneyeva,1 Sudthida Vasavanonda,1 Edith McDonald,2 Ayda Saldivar,1 Norm Wideburg,1 Xiaoqi Chen,1 Ping Niu,1 Chang Park,4 Venkata Jayanti,3 Brian Grabowski,3 G. Richard Granneman,5 Eugene Sun,6 Anthony J. Japour,6 John M. Leonard,6 Jacob J. Plattner,1 and Daniel W. Norbeck1

Departments of Infectious Diseases Research,1 Drug Analysis,2 Biotransformation,3 Structural Biology,4 Pharmacokinetics,5 and Antiviral Venture,6 Abbott Laboratories, Abbott Park, Illinois 60064

Received 16 April 1998/Returned for modification 5 August 1998/Accepted 11 September 1998

The valine at position 82 (Val 82) in the active site of the human immunodeficiency virus (HIV) protease mutates in response to therapy with the protease inhibitor ritonavir. By using the X-ray crystal structure of the complex of HIV protease and ritonavir, the potent protease inhibitor ABT-378, which has a diminished interaction with Val 82, was designed. ABT-378 potently inhibited wild-type and mutant HIV protease (Ki = 1.3 to 3.6 pM), blocked the replication of laboratory and clinical strains of HIV type 1 (50% effective concentration [EC50], 0.006 to 0.017 µM), and maintained high potency against mutant HIV selected by ritonavir in vivo (EC50, <= 0.06 µM). The metabolism of ABT-378 was strongly inhibited by ritonavir in vitro. Consequently, following concomitant oral administration of ABT-378 and ritonavir, the concentrations of ABT-378 in rat, dog, and monkey plasma exceeded the in vitro antiviral EC50 in the presence of human serum by >50-fold after 8 h. In healthy human volunteers, coadministration of a single 400-mg dose of ABT-378 with 50 mg of ritonavir enhanced the area under the concentration curve of ABT-378 in plasma by 77-fold over that observed after dosing with ABT-378 alone, and mean concentrations of ABT-378 exceeded the EC50 for >24 h. These results demonstrate the potential utility of ABT-378 as a therapeutic intervention against AIDS.

* Corresponding author. Mailing address: Abbott Laboratories, D-47B, Bldg. AP10, 100 Abbott Park Rd., Abbott Park, IL 60064-3500. Phone: (847) 937-1483. Fax: (847) 938-5034. E-mail: hing.l.sham{at}abbott.com.

Antimicrobial Agents and Chemotherapy, December 1998, p. 3218-3224, Vol. 42, No. 12
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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