The Body Covers: The 10th Conference on Retroviruses and Opportunistic Infections
Tenofovir Reduces Atazanavir/Ritonavir Parameters in Experienced Patients
February 12, 2003
Drug to drug interactions have become an important aspect in the selection of appropriate antiretroviral medications. Metabolism by cytochrome P450 can be the cause of many of the interactions seen with these agents. We all know that ritonavir (RTV, Norvir) is a potent inhibitor of Cyt P450 3A, which inhibits the metabolism of other protease inhibitors (PIs). This ability makes RTV an almost ideal partner for boosting the levels of other drugs metabolized by the same enzyme complex. Atazanavir (ATV or TAZ, Zrivada) is one of many PIs that benefit from this interaction. When boosted with RTV, the dose of ATV can be reduced to 300 mg, resulting in higher trough levels than with the standard 400-mg dose.
In this poster, presented by a French team, Dr. Taburet evaluated the pharmacokinetic parameters of a boosted ATV when given as part of a salvage regimen in combination with tenofovir DF (TDF, Viread) and other nucleosides. The patients in this study were participating in a larger trial (The Puzzle 2), in which three class-experienced patients, failing their therapy with an HIV RNA >1,000 copies/ml, were receiving this treatment.
After at least two weeks of no prior NNRTIs, 26 patients started treatment with boosted ATV (300/100) while continuing their previous NRTIs. Pharmacokinetic data was obtained two weeks later after a steady state to determine the baseline ATV and RTV levels. The regimen was then optimized with TDF and other NRTIs. A new ATV and RTV pharmacokinetic analysis was done at week six and compared with the baseline from four weeks earlier. Of the 26 patients initially randomized, only 10 subjects completed this part of the study.
The comparison between the RTV and ATV levels before and after the addition of TDF and the other optimized NRTIs showed a decrease in ATV levels. The ATV AUC decreased from 46,073 to 34,459 archiving a very weak statistical significance. The RTV levels also mildly decreased at week six (not statistically significant).
The authors suggested that this reduction could be the result of the addition of TDF in the regimen. They also acknowledged that the reduction in RTV levels at week six could have lowered the boosted effect for ATV, thus decreasing the drug exposure.
I cannot imagine any possible mechanism that would begin to explain how TDF could possibly be responsible for the pharmacokinetic difference on ATV levels from week two to week six. The metabolism of TDF occurs mainly through renal secretion and glomelar filtration. In fact, the lack of cytochrome P450 interaction is one of the positive attributes of this drug. Therefore, pharmacokinetic alterations with cytochrome P450 inducers or inhibitors should not have any effect on TDF, nor should TDF have any effect on the function of this system.
It is also unlikely that ATV would result in a significant decrease in the absorption of one of those PIs -- which could account for the differences seen in the ATV levels. Nevertheless, to my knowledge, those studies have not been conducted. (But I also question the need for them.)
There was also a very high inter-patient variability seen in all the levels obtained of ATV and RTV. In fact, in one patient there was no detectable RTV level at week six. That patient also showed a large decrease in the ATV levels at week six.
It is almost impossible to make anything out of this information. There are just too many factors that could have influenced that analysis, such as previous ART history, other nucleosides, advanced stage of the HIV disease (there was one patient with a CD4 count of 19 cells), adherence to the regimen, etc. There is also no theory postulated by the authors explaining how TDF could partially account for those results.
I certainly welcome studies that look at the dynamics between different regimens, and the pharmacokinetic interactions between drugs. But to weakly suggest that a drug may be responsible for an effect just because there is a temporal relationship in drug exposure is a stretch in my opinion.
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