February 12, 2003
As we are inundated with new once-daily (QD) antiretrovirals, the dilemma of which one to use and how to combine them becomes heated.
There are currently 17 approved antiretroviral medications, five of them with a QD indication (ddI, efavirenz, tenofovir, 3TC and d4T-ER), two more (abacavir and nevirapine) have good data supporting a QD dosing, and three more (atazanavir, 908 and FTC) are in the advance stage of development. So, by the end of the year, we may be looking at a list of 10 QD agents! This is great news -- now the issue of how to combine them and what their pharmacokinetic (PK) interactions are becomes interesting.
One of the most curious PK dynamics between these agents is the unexpected pharmacokinetic interaction between ddI (didanosine, Videx) and tenofovir DF (TDF, Viread). ddI is indicated to be taken on an empty stomach, while TDF was released with a light meal restriction. Previous studies have shown that taking ddI with food reduces the area under the curve (AUC) by 18-27 percent. However, early Gilead data showed that TDF could increase ddI levels by almost 40 percent. So, what happens when both drugs are taken in combination was of some interest.
To answer that question a formal study, presented last year in Barcelona, was conducted. In that study the PK of both ddI (400 mg EC) and TDF (300 mg) was measured when both drugs were taken simultaneously with a light meal (373 cal/20 percent fat) in healthy volunteers. The ddI AUC increased by 60 percent (with a range of 43-78). There were no alterations on the PK of TDF.
This new information prompted many clinicians to dose reduce ddI-EC to 250 mg when co-administrated with TDF. In fact, without the dose modification, several anecdotal cases of pancreatitis were reported by some HIV practices.
In this study, presented by Brian Kearney from Gilead, a formal assessment of that dose reduction was performed. In this study, he also compared the PK interactions after co-administering TDF 300 mg and ddI-EC 250 mg with a light meal, in a fasted state, and when both are administered staggered as per current label recommendations.
The results of the study showed that a staggered administration, per current label, (using ddI-EC 400 mg) resulted in an AUC equivalent to the administration of ddI-EC 400 alone.
The simultaneous co-administration of TDF and ddI-EC 250 mg in fasted state resulted in an increase of ddI Cmax of 14 percent, while co-administration in a fed state resulted in a decrease of ddI AUC of 11 percent. But, more interestingly, the administration of ddI-EC 250 mg with TDF staggered or simultaneously with or without a meal resulted in similar drug exposure to ddI-EC 400 mg alone (as calculated by the geometric means relative to the 400 mg alone, with values within the 90 percent CI).
No information was reported on the TDF levels in this study on fed and fasted states. Although TDF was approved with a light meal restriction, in the future, I would like to see more information on the TDF levels on a fasted state when in combinations with other RTs.
I take all this information as good news. Although in my practice, the combination of ddI and TDF is not frequently used, I have several patients who are currently taking this combination and in the future I may have more as treatment strategies become more complex. It is nice to see that a study supporting the appropriate dose adjustment was conducted. With these results it is clear that the formal indication for TDF and ddI co-administration is reducing the dose of ddI-EC to 250 mg. Better yet, it is the fact that we can administer both drugs with a light meal.
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