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The Body Covers: The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Antiretroviral Agents: Adherence, Pharmacokinetics and Pharmacodynamics (Poster Session 175)

December 18, 2001

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

  • An Assessment of Plasma Amprenavir (APV) Pharmacokinetics (PK) Following Administration of Two GW433908 (908) and Ritonavir (RTV) QD Regimens in Combination with Efavirenz (EFV) in Healthy Adult Subjects (APV10009)
    Abstract 1737
    Authored by M. B. Wire (Glaxo Wellcome, RTP, NC), S. L. Preston (Albany Medical College, Albany, NY), C. Ballow (Buffalo Clinical Research Center, Buffalo, NY), C. W. Hendrix (Johns Hopkins University School of Medicine, Baltimore, MD), Y. Lou (Glaxo Wellcome, RTP, NC), P. Piliero (Albany Medical College, Albany, NY), D. S. Stein (Glaxo Wellcome, RTP, NC)
    View the original abstract

In an attempt to control viral replication in patients exposed to several antiretroviral drugs, physicians are getting very creative in the way we combine some HIV medications. It is quite common to see today the combination of two protease inhibitors as a part of HAART, or at least the use of a mini-dose of ritonavir (RTV) to enhance the potency of another protease inhibitor. The benefits of combining amprenavir (APV) and ritonavir (RTV) have been extensively studied. (See abstract 489.)

GW 433908 (or just "908") is a new formulation, or pro-drug, of amprenavir that is more water soluble, which eliminates the need for a complicated formulation. (See The Body's coverage from the 8th Conference on Retroviruses and Opportunistic Infections.) The safety and efficacy of "908" 1,400 mg to be used once a day is currently under study. "908" 1,400 mg (two capsules of 700 mg each) is equivalent to amprenavir 1,200 mg.

When we try to combine two protease inhibitors, such as "908" (APV) and ritonavir, with an NNRTI, the situation becomes even stickier. It is a real pharmacokinetic challenge to predict the interactions of all these drugs. That is why we need studies like this one, in which the level of all these drugs combined is actually measured.

Efavirenz (EFV), commercially known as Sustiva, is a potent inducer of the amprenavir metabolism. Efavirenz can decrease the plasma amprenavir area under the curve (AUC) and amprenavir Cmax by 24 percent and 33 percent respectively. Thus, when combining amprenavir with efavirenz it is necessary to increase the amprenavir dose to compensate for this reduction. Ritonavir, on the other hand, has an overall effect of increasing amprenavir levels. When combining these three drugs (APV, EFV and RTV) it may be possible to compensate for the reduction in amprenavir levels caused by efavirenz with the addition of more ritonavir. The challenge is to figure out how much of these drugs we have to use to obtain an effective and safe drug level.

The purpose of this study was precisely that -- to provide plasma amprenavir PK data to aid in the selection of the appropriate dose of both "908" and ritonavir when co-administered with efavirenz.

Twenty-two HIV-negative healthy adults were given "908" 1,400 mg plus ritonavir 200 mg once a day for two weeks. On day 15 all subjects were randomized 1:1 to receive "908," efavirenz and either ritonavir 200 mg once a day or ritonavir 300 mg once a day. Amprenavir PK levels were measured at several intervals during the study.

Steady State Plasma Amprenavir PK

Plasma APV PK

908 plus RTV 200 mg (at day 14) 908 plus EFV plus RTV 200 mg (at day 28) 908 plus EFV plus RTV 300 mg (at day 28)
C max
C t,ss

There were no significant differences in the type or number of adverse events between the subjects receiving ritonavir 200 mg versus ritonavir 300 mg, but there was a significant increase in both groups in fasting cholesterol and triglycerides after two weeks of "908," efavirenz and ritonavir.

My initial impression when I was reading this poster was that ritonavir 200 mg dose was going to be sufficient to counteract the CYP3A4 induction effect of efavirenz on amprenavir metabolism. I was very surprised to learn that an extra 100 mg of ritonavir (total ritonavir 300 mg) was needed to maintain plasma amprenavir concentrations comparable to that achieved with "908" and ritonavir once a day (without efavirenz).

This study -- at least for me, an optimistic reviewer -- was not an eye-opener but rather a reaffirmation that we should not be guessing on pharmacokinetic levels when combining different pharmaco-agents with similar pathways of metabolism.

I need to point out that the recommended dose of ritonavir, when used in combination with the currently available amprenavir (agenerase) and efavirenz, is still 200 mg once a day. For "908" (the new formulation of APV in development) with efavirenz, an extra 100 mg of ritonavir may be required to achieve better drug levels.

I presume that patients who will be taking this complex regimen are patients with vast experience and resistant HIV. To gain the most benefit from this type of regimen it is important for both patient and physician to recognize the best therapeutic dosages for these drugs when using them simultaneously.

A note from The field of medicine is constantly evolving. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

See Also
More Research on HIV/AIDS Treatment Strategies

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