[6] RESISTANCE PROFILES OF SECOND GENERATION HIV PROTEASE INHIBITORS DPC 681 AND DPC 684

5th International Workshop on HIV Drug Resistance & Treatment Strategies

4-8 June 2001, Scottsdale, Arizona

[TITLE:] RESISTANCE PROFILES OF SECOND GENERATION HIV PROTEASE INHIBITORS DPC 681 AND DPC 684

[AUTHOR(S):] LT Bacheler¹, S Jeffrey¹, K Logue¹, S Garber¹, S Diamond¹, R Kaltenbach¹, G Trainor¹, D Getman² and S Erickson-Viitanen¹
¹ DuPont Pharmaceuticals Company, Wilmington, Del., USA; and ² GD Searle (now Pharmacia), St Louis, Mo., USA
Antivir Ther. 2001;6 Suppl 1:5

HIV protease inhibitors (PIs) are important components of many HAART regimens. There is now a growing and unmet need for second generation PIs able to inhibit viruses that have developed resistance to some or all of the currently marketed PIs. Two such potential inhibitors, DPC 681 and DPC 684 have been identified and evaluated. DPC 681 and DPC 684 are highly potent HIV protease inhibitors with an average IC₉₀ of 4–8 nM against wild-type viruses. Antiviral potency was maintained against non-clade B isolates and a Group O isolate. DPC 681 and DPC 684 were highly potent against PI resistant viruses created by site-directed mutagenesis, with no loss in potency against a nelfinavir-resistant D30N mutation or a saquinavir-resistant M48V/L90M mutant, and =6.5- (DPC 681) or =3.5-fold (DPC 684) loss in potency against viruses with 3–5 amino acid substitutions which were highly resistant to other PIs. Clinically derived recombinant viruses (n=30, 67% resistant to = 4 PIs) from patients who had failed PI containing regimens and which contained 3–11 substitutions in the protease gene had median IC₅₀s of 10 nM (range 0.7–160 nM) for DPC 681 and 11 nM (range 0.5–37 nM) for DPC 684. Against the same panel of PI-resistant clinical isolates, median IC₅₀s for currently approved PIs varied from 77 nM (range 1.8–813 nM) for lopinavir, 135 nM (range 12–590 nM) for amprenavir, and 144 nM for saquinavir (range 2.6 nM to >300 nM) to 550 nM (range 12.5 nM to >1.3 μM) for indinavir and 1 μM (range 25 nM to >1.3 μM) for nelfinavir. The extent of protein binding in human serum was quantitated by equilibrium dialysis. DPC 681 and DPC 684 were 98.4 and 98.1% proteinbound, respectively. These results suggest that human plasma levels of 0.7 μM (DPC 684) to 1 μM (DPC 681) total drug would yield significant suppression of 90% (DPC 681) or all (DPC 684) of the PI-resistant clinical isolates assessed to date.

PRESENTING AUTHOR: LT Bacheler

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