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

Abstract

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.

An Integrated Pharmacokinetic Model for the Influence of CYP3A4 Expression on the In Vivo Disposition of Lopinavir and Its Modulation by Ritonavir

“…The PI ritonavir is a potent inhibitor of CYP3A4-mediated metabolism and thereby increases the exposure to lopinavir. [1][2][3] The inhibition of CYP3A4 by ritonavir has been investigated in both in vivo and in vitro but the exact mechanism of CYP3A4 inhibition by ritonavir remains unclear. It is thought that CYP3A4 inhibition by ritonavir is both time and concentration dependent.…”

From Saquinavir to Darunavir: The Impact of 10 Years of Medicinal Chemistry on a Lethal Disease

“…Ritonavir, their first HIV PI, showed strong inhibition of PGP pumps and P-450 enzymes. For lopinavir, the results were spectacular; in the absence of ritonavir, only low plasma levels of lopinavir could be obtained in animals and volunteers [13]. In the presence of ritonavir, twice daily administration of lopinavir resulted in sustained high plasma levels for 24 h. The clinical results were very good: a large fraction of the patients on lopinavir/ritonavir-based treatment showed complete suppression of the virus for years.…”

“…Continued efforts resulted in a series of molecules with highly diverse P2 and P2 0 ligands. Some of them like the tetrahydrofuran and the p-aminosulfonyl groups of amprenavir [12] made H-bonds to the backbone of the enzyme, others like the 2,6-dimethylphenoxyacetyl of lopinavir [13] optimized lipophilic binding. Amprenavir and lopinavir remained clearly active on a number of mutated viruses that appeared quite frequently.…”

Drug interactions with antiretrovirals

“…This potent PI is metabolized primarily via CYP450-3A. The combination of low doses of ritonavir (eg, 100 mg twice daily) has been used to sustain plasma concentrations of ABT-378 in excess of IC 90 values for HIV strains with reduced susceptibility to other PIs [53]. The approved PIs are all substrates for cytochrome p450 but they have mixed effects on the degree of hepatic metabolism with regard to induction and inhibition of these enzymes.…”