• GW433908, a Novel Prodrug of the HIV Protease Inhibitor (PI) Amprenavir (APV): Safety, Efficacy, and Pharmacokinetics (PK) (APV20001) (Poster 333)
  Authored by R. Wood, K. Arasteh, R. Pollard, P. Kaur, O. Nadarer, and M. B. Wire
  View the original abstract

Amprenavir is a good drug with a bad formulation. The difficulties with solubility require that this drug be packed in very large pills, and eight of them have to be taken twice a day to get adequate levels. Amprenavir seems to be the most "lipid friendly" protease inhibitor and also the protease inhibitor that maintains a better "residual activity" when other protease inhibitors have failed; so it is usually used in salvage combination regimens for patients experiencing virologic failure.

The studies of Judy Fallon at the U.S. National Institutes of Health (NIH) showed that amprenavir could be combined with low-dose ritonavir, allowing an easier regimen of four capsules of amprenavir bid and 100mg of ritonavir to be used in combination. Very few people (if any) use this drug without the addition of ritonavir.

As soon as Glass/Vertex realized this problem with the formulation of amprenavir they struggled to find a solution (it is no fun having a drug that very few people can take).

GW433908 is the response to this problem. This is a prodrug of amprenavir that is more water-soluble, which eliminates the need for complicated formulation -- the culprit of the famous huge pills. This new formulation can be packaged in 465mg tablets (a very strange number). This study showed that the administration of this drug (three or four capsules bid) combined with abacavir and 3TC produced good antiretroviral responses at four weeks in 85 treatment-naive patients, and similar pharmacokinetics (not exactly proportional) than the old agenerase 1,200mg bid. Most of the patients in the study were South Africans. Tolerability was better with this new formulation.

Glaxo Inc. will still have to do more studies before this pro-drug gets full approval, but it looks like it is definitely an improvement over the old formulation. It is likely that many clinicians would like to use this new prodrug in combination with ritonavir, which will assure very high levels in blood. It would be ideal if this drug could be combined with ritonavir in the same pill, so that the number of pills taken are reduced, which will improve dosification and adherence, in a similar way to the Kaletra formulation. However, this is not expected to happen -- Abbott and Glaxo are two different companies, with different market interests.

We need good drugs for the rescue of protease failures. Amprenavir is a useful drug in that setting. When this new formulation is available, it will be an improvement and will facilitate the use of amprenavir in the management of patients with HIV infection.