Virtual Inhibitory Quotient Predicts Response to Ritonavir Boosting of Indinavir-Based Therapy in Human Immunodeficiency Virus-Infected Patients with Ongoing Viremia

Abstract

Depending on the degree of underlying resistance present, optimization of the pharmacokinetics of protease inhibitors may result in improved virologic suppression. Thirty-seven human immunodeficiency virus (HIV)-infected subjects who had chronic detectable viremia and who were receiving 800 mg of indinavir three times a day (TID) were switched to 400 mg of indinavir BID with 400 mg of ritonavir two times a day (BID) for 48 weeks. Full pharmacokinetic evaluations were obtained for 12 subjects before the switch and 3 weeks after the switch. Combination therapy increased the indinavir predose concentrations in plasma by 6.47-fold, increased the minimum concentration in serum by 3.41-fold, and reduced the maximum concentration in serum by 57% without significantly changing the area under the plasma concentration-time curve at 24 h. At week 3, 58% (21 of 36) of the subjects for whom postbaseline measurements were available achieved a viral load in plasma of <50 copies/ml or a reduction from the baseline load of > or =0.5 log(10) copies/ml. Of these subjects, 82% (14 of 17) whose viruses had three or fewer protease inhibitor mutations and 88% (14 of 16) whose viruses had an indinavir virtual phenotypic susceptibility test of more than sixfold less than that for the baseline isolate were considered virologic responders. The indinavir virtual inhibitory quotient, which is a function of baseline indinavir phenotypic resistance (estimated by virtual phenotype) and the indinavir predose concentration in plasma achieved with indinavir-ritonavir combination therapy, was the best predictor of a viral load reduction. Sixteen subjects discontinued the study by week 48 due to adverse events, predominantly related to hyperlipidemia. Pharmacokinetic intensification of indinavir-based therapy with ritonavir reduced the viral loads in subjects but added toxicity. The virtual inhibitory quotient, which incorporates both baseline viral resistance and the level of drug exposure in plasma, was superior to either baseline resistance or drug exposure alone in predicting the virologic response.

Amide hydrogen exchange in HIV–1 subtype B and C proteases – insights into reduced drug susceptibility and dimer stability

“…The M36I mutation is the only polymorphic mutation in the C-SA protease that is associated with drug resistance to most of the FDAapproved PIs in combination with ritonavir [41]. This mutation is associated with virological failure or a reduced virological response to atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, saquinavir and tipranavir in combination with ritonavir [42][43][44][45][46][47][48][49]. Mutations at residue position 89 are associated with virological failure to darunavir and tipranavir in combination with ritonavir [44,50], and mutations at resi- In the subtype B protease (A) (PDB ID: 2PC0 [13]), M36 appears to provide anchorage for E35, and stabilizes the salt bridge between E35 and R57.…”

“…Polymorphic sites of the subtype B protease (PDB ID: 2PC0) [13] and the C-SA protease (PDB ID: 3U71) [37]. The flexible flaps of the protease (residues at positions [46][47][48][49][50][51][52][53][54] are coloured cyan. The fulcrum region (residues at positions 10-23), hinge region (residues at positions 35-42 and 57-61) and cantilever region (residues at positions 62-78) are implicated in flap opening.…”

Lung Cancer in HIV Infection

“…[79][80][81] All protease inhibitors inhibit CYP4503A4, but ritonavir is the most potent inhibitor in the class, even at low doses. 82 Also, ritonavir inhibits the P-glycoprotein efflux pump protein, driving chemotherapeutic agents like vinca alkaloids and taxanes outside the cells. 83 Nucleoside analogs like zidovudine can exacerbate myelosuppression.…”

Pharmacokinetic Enhancement of the Hepatitis C Virus Protease Inhibitors VX-950 and SCH 503034 by Co-Dosing with Ritonavir

“…However, since HIV PIs are primarily or exclusively metabolized by the cytochrome P450 (CYP) 3A system, their plasma levels are markedly enhanced and prolonged by co-dosing with ritonavir, a potent CYP3A inhibitor (Kempf et al, 1997;King et al, 2004). The pharmacokinetic boosting of HIV PIs with ritonavir increases antiviral efficacy, allows twice-or once-daily dosing, and delays or prevents the emergence of drug resistance (Kempf et al, 2004;Shulman et al, 2002). To assess the potential to enhance VX-950 and SCH 503034 plasma levels, we evaluated their interactions with ritonavir in preclinical metabolism and pharmacokinetic models.…”