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Ritonavir Increases Plasma Levels of Other HIV Protease Inhibitors in Animal Models
Abstract 143
Coadministration with Ritonavir Enhances the Plasma Levels of HIV Protease
Inhibitors by Inhibition of Cytochrome P450.
Authors: D Kempf, K Marsh, J Denissen, G Kumar, D Rodrigues, E McDonald, C Flentge, B Green, X Chen, J Leonard and D Norbeck.
It has been recently discovered that ritonavir is a potent inhibitor of the
cytochrome P450 system which led, in part, to the explanation of its favorable
pharmacokinetic profile. Results of pharmacologic interactions between ritonavir
and other peptiomimetic HIV protease inhibitors observed in animal models
were reported here.
Ritonavir when given together with other protease inhibitors in laboratory animals resulted in significant elevation of the plasma levels of each inhibitor without any effect on the plasma levels of ritonavir. The co-administration of ritonavir with saquinavir produced an enhancement of saquinavir plasma level by about 29,000% over 8 hours. The following enhancement of other protease inhibitors was also seen with ritonavir over 8 hours: indinavir (about 800%), nelfinavir (about 1,000%) and 141W94 (about 800%).
Dr. Kempf mentioned that combination therapy of ritonavir and other peptidomimetic protease inhibitors is likely to produce a sustained antiviral effect in vivo. The pharmacokinetic enhancement is expected to be more pronounced with protease inhibitors having different resistance profiles.
COMMENTS: A pilot study of ritonavir in combination with saquinavir in HIV-infected people was initiated. Results from this study should provide guidance for selected people who are interested in starting such combination regimen.
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