Anderson PL, Bushman LR, Kakuda TN, Remmel RP, Brundage RC, Fletcher CV; Conference on Retroviruses and Opportunistic Infections.

7th Conf Retrovir Oppor Infect Jan 30 Feb 2 2000 Conf Retrovir Oppor Infect 7th 2000 San Franc Calif. 2000 Jan 30-Feb 2; 7: 94 (abstract no. 101).

Univ. of Minnesota, Minneapolis.

Background: Protein binding has been shown to decrease the anti-HIV activity of protease inhibitors (PIs) in vitro, consistent with the theory that the unbound concentration represents the fraction available to exert a pharmacologic effect. The objectives of this study were to: (1) quantitate IDV unbound (Cu) and total (Ct) concentrations, (2) characterize protein binding in HIV-infected persons, and (3) investigate relationships between Cu and Ct with anti-HIV effect. Methods: Nine, 8-hour, steady state, pharmacokinetic profiles were obtained in 5 subjects; 4 subjects had 2 profiles 6 months apart. Membrane ultrafiltration was used to separate the unbound fraction of IDV in plasma. IDV Cu and Ct were quantified with HPLC. In a separate cohort of 23 HIV-infected adults all receiving IDV 800 mg q8h, IDV Cu and Ct at 5-hours post dose were determined. These values were compared in those persons with undetectable (<400 copies/mL) vs. detectable plasma HIV RNA. Results: For the 9 intensive profiles, the mean protein binding across all time points was 65.4% (SD 3.5%; range 56.9-74.3%). There was no evidence of concentration dependent protein binding over the IDV Ct range of 60.8-15197 ng/mL. In the 4 patients with 2 profiles 6 months apart, the % difference in binding ranged from 0.2-8.3%. In the 23 patient cohort, the median 5-hour IDV Ct was 538 ng/mL in those with undetectable (n=14) HIV RNA vs. 310 ng/mL in those with detectable (n=9) HIV RNA (P=0.03, Mann-Whitney U). Median IDV Cu were 230 ng/mL compared with 121 ng/mL in the undetectable and detectable groups, respectively (P=0.05, Mann-Whitney U). Conclusions: The 57-74% range in protein binding of IDV in these HIV-infected subjects is generally consistent with the 60% binding reported in the literature, which is based on in vitro studies. IDV protein binding was stable over a 6-month period. IDV 5 hour Ct and Cu were higher in subjects with undetectable vs detectable HIV-RNA. This work to quantify unbound concentrations opens new leads, relevant to all PIs and NNRTIs, to understand more precisely concentration-effect relationships.

Publication Types:

• Meeting Abstracts

Keywords:

• AIDS Vaccines
• Acquired Immunodeficiency Syndrome
• Adult
• HIV Infections
• HIV Protease Inhibitors
• HIV Seropositivity
• Humans
• In Vitro
• Indinavir
• Protease Inhibitors
• organization & administration

Other ID:

• GWAIDS0005482

UI: 102242979

From Meeting Abstracts