AEGiS-15IAC: Maintenance of favorable in vitro metabolic profile of atazanavir when combined with low dose ritonavir.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Maintenance of favorable in vitro metabolic profile of atazanavir when combined with low dose ritonavir.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. ThOrB1356)

Noor MA, Mulvey R, Wang S, Elosua C, Wang F, Parker RA, Flint OP
Bristol-Myers Squibb Company, Princeton, NJ, United States

BACKGROUND: Treatment of HIV with some protease inhibitor (PI) drugs is associated with metabolic complications including insulin resistance and type 2 diabetes. A proposed mechanism is by blockade of insulin-responsive glucose transporter (GLUT4). Atazanavir (ATV) is a new PI that is not associated with insulin resistance and does not block glucose uptake through GLUT4 in vitro. Clinically, increasing number of patients are being treated with combination of low-dose ritonavir (RTV) (mean Cmax mu0.5 to 1.5 muM) added on to ATV to take advantage of enhanced pharmacokinetic profile. We tested the hypothesis whether low dose RTV would negate the favorable metabolic profile of ATV previously reported in vitro.

METHODS: GLUT activity was assayed as [3H]2-deoxyglucose uptake following insulin stimulation in the mouse or rat primary adipocytes cell models as described previously. Glucose uptake was quantified in the presence of atazanavir in combination with ritonavir at various doses to approximate concentrations expected in patients.

RESULTS: As single drugs at therapeutic plasma concentration (>10 muM), ritonavir but not atazanavir exhibited rapid, concentration-dependent GLUT inhibition. These concentrations are near maximum plasma concentration when therapeutic doses of RTV (600 mg twice daily) are used in patients. ATV at therapeutic concentration alone and in combination with RTV at concentrations (≤ 3 muM) observed with pharmacologically enhanced ATV, did not inhibit GLUT activity. Percent activity is shown below: [table: see text]

CONCLUSION: ATV when used in combination with low dose RTV (≤ 3 muM) maintains its favorable profile in this cell model of glucose uptake. The data are consistent with the current hypothesis that RTV boosted ATV used clinically will maintain the favorable metabolic profile of unboosted atazanavir. Clinical data are needed to confirm these findings.

Keywords: AEGIS, Ritonavir, Pyridines, HIV Protease Inhibitors, Oligopeptides, HIV Infections, HIV, HIV Protease, Anti-HIV Agents, Acquired Immunodeficiency Syndrome, Protease Inhibitors, atazanavir, In Vitro, Animal, Mice, Humans, Rats, metabolism

040711
ThOrB1356