December 16, 2001
This study presents a new twist on the many well-documented benefits of combining amprenavir (APV) with ritonavir (RTV).
Over the past few years we have learned to appreciate the complexity of interactions between protease inhibitors and the cytochrome P-450. These interactions can become even more complex when two or more protease inhibitors are combined.
As we all know, both amprenavir and ritonavir are substrates and inhibitors of the cytochrome P450-3A4 (CYP 3A4). By now everyone will agree that in HIV-infected patients, mini-dose boosting ritonavir (100mg BID) allows for a high plasma amprenavir exposure and a higher Cmin, all this while reducing pill burden.
Unfortunately, things are not that simple and other factors need to be considered when attempts are made to predict pharmacokinetic (PK) levels. Other mechanisms have been identified that can significantly affect the intracellular drug concentrations. This study explores one of these other factors.
Glycoprotein-P (P-gp) is an efflux protein that is actually produced by the multi-drug resistance gene (MDR-1). P-gp is distributed in normal tissues, where it could either result in reduced drug absorption (gastrointestinal tract, blood brain barrier, or lymphocyte cells), or enhance drug elimination (in the kidney). Studies have shown that ritonavir can inhibit this glycoprotein function, thus further improving the intracellular concentrations (IC) at target sites of other drugs such as amprenavir.
This study by Dr. Garraffo and colleagues is a pharmacokinetic study (phase I) in HIV-positive patients looking to measure the plasma and intracellular concentrations of amprenavir when co-administered with ritonavir either once or twice daily. Ten HIV-infected patients participated in this study for at least ten days, receiving either amprenavir 1,200mg BID, amprenavir 600/ritonavir 100mg BID, or amprenavir 1,200/ritonavir 200mg QD. Multiple blood samples were taken to measure amprenavir and ritonavir PK levels at various intervals. Amprenavir intracellular concentrations in PBMCs were also collected.
This table shows the PK results of the different amprenavir and ritonavir combinations:
APV PK Parameters
|APV BID||APV/RTV BID||APV/RTV QD|
As expected, the low dose of ritonavir significantly increased amprenavir plasma concentrations. Furthermore, amprenavir clearance was decreased by more than 50 percent.
What was nice about this study is that it also showed evidence of ritonavir contributing in maintaining significant intracellular amprenavir concentrations. The combination of amprenavir 1,200/ritonavir 200mg QD produced an acceptable amprenavir Cmin value, that was well above the IC50.
This study did not specifically correlate the increases of the intracellular concentration of amprenavir in the inhibition of P-glycoprotein by ritonavir, but rather it suggests this pathway as a potential explanation. Although clinical correlation in terms of viral suppression was not an objective in this study, there is ample data presented at other conferences on the clinical relevance of using or switching to amprenavir/ritonavir combination. At the 8th Conference on Retroviruses and Opportunistic Infections, an investigator at Glaxo presented their data in the amprenavir 2001 study. In that study, switching amprenavir 1200mg BID to amprenavir 600mg/ritonavir 100mg or amprenavir 1200mg/ritonavir 200mg QD allowed a reduction of the total daily dose of amprenavir (from 16 to 8 capsules daily) while maintaining virologic suppression.
Overall, this is a good study that added more data to correlate with what other studies have shown on the advantages of using amprenavir and ritonavir in combination and why we should consider amprenavir/ritonavir QD in clinical practice. I personally have stopped prescribing amprenavir alone, and I only use it in combination with ritonavir once or twice daily.
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