July 11, 2002
Tenofovir DF (TDF, Viread) is the newest medication approved for the treatment of HIV infection. The medication is dosed once-daily and has fueled interest in wholly once-daily HAART medications. In order to achieve this, TDF needs to be dosed with other once-daily medications.
An obvious candidate partner for TDF would be didanosine (ddI); unfortunately, earlier pharmacokinetic studies (evaluation of the way the body absorbs and metabolizes) using the older buffered tablet form of ddI showed an unexpected 28 to 44 percent increase in ddI levels when taken with TDF. This observation raised questions about the safety of the co-administration of the two drugs, given concern about potential serious nerve or pancreatic injury with higher doses of ddI.
The new, enteric-coated formulation of ddI (ddI EC, Videx EC) is a simpler, better tolerated form of ddI. ddI EC's drug exposure is reduced between 18 and 27 percent when taken with food, suggesting that taking TDF and ddI EC, together with food, could offset the increase in ddI blood levels.
This study was a Phase I, open-label study to evaluate the drug interactions between TDF and ddI EC with meals. Non-infected adult subjects were studied. Results of the study confirmed an earlier study that showed that ddI had no significant effect on TDF levels. Surprisingly, taking TDF (300 mg) with ddI EC (400 mg;) either together or two hours apart with a light meal caused a 48 to 64 percent increase in ddI exposure compared with ddI EC taken alone in the fasted state.
These data are important for healthcare providers, since many patients might be interested in a simple, low pill count, once-daily regimen that included TDF and ddI EC. Possible limitations of the study are worth noting, particularly the analysis of drug levels among non-infected persons and the relatively small sample size of the study. Indeed, if there is a message from this study, it is one of scientific humility -- that what we may reasonably expect, based on assumptions, may not be correct.
Perhaps not impossible to overcome, the TDF-ddI drug interaction issue and its possible risks need to be weighed heavily when counseling patients about treatment options. An alternative view could be that increased ddI levels, when taken with TDF, might be of particular benefit to patients and healthcare providers looking for a way to maximize ("boost") ddI drug levels -- as in patients with multi-drug resistant virus. All of these points remain speculative until the appropriate studies are performed.
Another point of interest is the already approved use of lamivudine (3TC, Epivir) as a 300 mg once-daily medication in Europe -- this will likely be approved in the United States as a once-daily medication in the near future. Other nucleoside medications -- such as stavudine (d4T, Zerit), abacavir (Ziagen) and zidovudine (ZDV, AZT, Retrovir) -- are also under investigation as once-daily medications; extended-release stavudine (Zerit XR) will likely seek approval by the U.S. Food and Drug Administration in the near future. Taken together, these future reverse transcriptase inhibitors might provide alternative once-daily partners for TDF.
It is entirely possible that dosing TDF with a lower dose of ddI (either 250 or 300 mg) might completely obviate this problem -- this study has not yet been performed, though the concept has undoubtedly generated interest among the two drug manufacturers. Until that time and data presentation come, I will proceed and counsel with caution.
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