7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 13–16 November 2005, Dublin, Ireland

A single dose of amprenavir does not induce insulin resistance in healthy normal volunteers

GA Lee, MN Rao, JM Schwarz, FT Aweeka and C Grunfeld
University of California San Francisco, San Francisco, CA, USA

Antiviral Therapy 2005; Supplement 3:L11 (abstract no. 15)

BACKGROUND: Previously, we showed that single doses of indinavir or ritonavir decreased insulin-mediated glucose disposal in healthy normal volunteers, providing evidence that some HIV protease inhibitors can cause insulin resistance in the absence of HIV infection, hyperlipidaemia or changes in body composition. In the present study, we examined the effect of a single dose of amprenavir, which has been reported not to affect insulin-mediated glucose disposal in humans.

METHODS: In this randomized, double-blind, cross-over study, a single dose of amprenavir 1200 mg or placebo was given to six healthy HIV-negative men 1 h before assessment of insulin sensitivity by euglycaemic hyperinsulinaemic clamp. Subjects reached therapeutic amprenavir levels at the start of the clamp. Free fatty acid levels and substrate oxidation rates were measured during each clamp experiment.

RESULTS: There were no significant differences in body weight, fasting plasma glucose, serum insulin or lipid levels before each clamp experiment. During steady-state (t120 to 180 min), serum insulin reached levels of 621±30 vs 610±36 pmol/l (P=0.46) during amprenavir and placebo administration, respectively. Glucose was maintained at approximately 4.4 mmol/l under both conditions. Plasma amprenavir levels reached 6.6±0.8mg/l at the start of the clamp, declined to 2.9±0.4 mg/l 1 h after the start of the clamp and remained >2.0mg/l until the end of the experiment, mimicking amprenavir therapeutic pharmacokinetics. Insulin-mediated glucose disposal was 8.5±1.2 vs 8.4±1.0mg/kg*min per µU/ml insulin with placebo and amprenavir, respectively (P=0.8). The non-oxidative component of total glucose disposal also did not change with either placebo or amprenavir administration (5.1±1.0 vs 5.2±0.6 mg/kg*min; P=0.8). Free fatty acid levels were not significantly different at baseline and were suppressed similarly with insulin administration during both experiments.

CONCLUSIONS: A single dose of amprenavir in HIV-negative men did not decrease insulin-mediated glucose disposal as assessed by the euglycaemic hyperinsulinaemic clamp. Relatively lower therapeutic levels of amprenavir may explain why amprenavir inhibits GLUT4 in vitro, but does not inhibit insulin-mediated glucose disposal.

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2005-11-13
15

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