Pharmacodynamics of Antimicrobials I: In Vitro Models (Poster Session 216)
- In Vitro Model for Antiviral Activity for Amprenavir (APV)/Ritonavir (RTV)
Authored by S. L. Preston (Alb Med Coll, Albany, NY), P. J. Piliero (Alb Med Coll, Albany, NY), J. A. Bilello (Alb Med Coll, Albany, NY), B. M. Sadler (GSK, RTP, NC), D. S. Stein (GSK, RTP, NC), G. L. Drusano (Alb Med Coll, Albany, NY)
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We must be certain that the antiretroviral drugs that we administer are effective in suppressing viral replication. Notwithstanding issues around adherence, tolerability, cost and access, we have to ensure that, once taken, these drugs produce blood levels that will suppress HIV. And these blood levels need to be above (maybe well above) a concentration threshold for antiviral activity at all times in all people taking antiretroviral therapy (ART). If the drugs fail to achieve these blood levels, not only will viral replication not be suppressed, but antiretroviral resistance will occur. And this will further complicate antiretroviral therapy.
One approach that can be used with protease inhibitors is the boosting or enhancing of blood levels with the use of other drugs such as ritonavir or delavirdine. Ritonavir (RTV), which is widely used for this purpose, inhibits a cellular enzyme system that is responsible for the metabolism of the target protease inhibitors. With this metabolic inhibition we then see the boosting effect.
Specifically, we see higher and, more importantly, more prolonged blood levels of the target protease inhibitor. This has had the effect of enhancing protease inhibitor antiretroviral activity and improving the dosing of the protease inhibitor. For example, by combining a relatively small amount of ritonavir (100 mg; one capsule) with indinavir, the indinavir can be taken twice a day with food rather than three times a day on an empty stomach. And the activity of indinavir is increased, producing a more useful drug that is taken less often with fewer pills.
This study from Albany Medical Center in Albany, N.Y. and GlaxoSmithKline in North Carolina provides a new laboratory method of evaluating the effect of combining ritonavir with amprenavir. If this new method is successful, it will be applicable to other combinations of protease inhibitors.
So what did they do? They devised a method, the hollow-fiber system, to measure the effects of amprenavir/ritonavir on HIV replication in infected human cell lines in cell culture. They also used human volunteers for measurement of blood levels ("pharmacokinetic sampling") after seven days of administration of amprenavir (450 mg twice daily) or ritonavir (300 mg twice daily) followed by seven days of both. The sampling was done on day 14. From the hollow-fiber system, they showed that HIV suppression was a function of the time that the drug concentration was greater than the EC95 (the concentration required to inhibit growth of 95 percent of viral isolates; a standard measure of the potency of an antiretroviral drug). They then showed that this dose combination of amprenavir/ritonavir (450/300 mg bid) was able to attain blood concentrations of APV to inhibit 93 percent of wild-type strains and 57 percent of strains from heavily pretreated patients (i.e., multiresistant strains). They predicted that a full regimen using amprenavir/ritonavir with two NRTIs would improve the ability to attain viral suppression.
Is this study important? In my opinion, yes and no. This combination would utilize a small dose of amprenavir, which should help adherence and tolerability. But the combination includes a relatively high dose of ritonavir, which might impair adherence and tolerability. As a model for testing different doses and different combinations (prior to clinical testing in patients), however, this method should be very useful. And both the pharmacologists studying pharmacokinetics of antiretroviral drugs and the clinicians administering them need more ways to test them.