• Tenofovir DF (TDF) and Didanosine EC (ddI EC): Investigation of Pharmacokinetic (PK) Drug-Drug and Drug-Food Interactions
  Authored by B.P. Kearney
  Poster 932

Background

Tenofovir (TDF, Viread) is a nucleotide and ddI (didanosine, Videx) is a nucleoside. Both may be used as the backbone of HIV therapy with either a non-nucleoside or a protease inhibitor. Tenofovir has been increasingly used in antiretroviral therapy following the results of study 903. This study looked at the regimen of tenofovir/3TC (lamivudine, Epivir)/efavirenz (EFV, Sustiva), and, at 48 weeks, more than 85 percent of study participants were able to reach a viral load below 400 copies.

ddI is a highly effective antiviral also available for once-daily dosing. However, due to the food restrictions with ddI (it has to be taken without food, in a fasted state), many individuals have chosen alternative therapies that they find easier to comply with. ddI has to be administered in the fasting state because the area under the curve (i.e., exposure) is reduced by approximately 25 percent when taken with food.

However, previous evidence has suggested that when tenofovir is dosed with ddI, a drug interaction occurs which leads to higher levels of ddI. Because of these results, it has been suggested that the dose of ddI should be reduced when used with tenofovir, and that it may be possible to remove the food restrictions with ddI. This would clearly lead to the possibility of an easy-to-take nucleoside/nucleotide backbone of tenofovir/ddI, which could be taken once daily, and ease the compliance problems associated with ddI therapy while providing a potentially highly effective backbone.

Aim

The aim of this study was to measure the pharmacokinetic (PK) interaction with ddI/tenofovir when administered together either with a light meal or in a fasting state.

Results

Twenty-eight individuals entered this study. Fourteen were male and 14 female. The majority were Caucasian. Administration of ddI together with tenofovir either in the fasting state or with a light meal made no difference to the tenofovir PK. However, in individuals where ddI was administered at the full dose of 400 mg with a light meal, together with tenofovir, there was an increase in the Cmax (the maximum level of ddI reached) from 1,050 ng/mL to 1,720 ng/mL, and the area under the curve (i.e., total exposure) from 3,160 ng/mL to 5,060 ng/mL. No serious adverse events occurred during the study period over 15 days.

Conclusion

The conclusion of the study was that co-administration with tenofovir and ddI with a light meal did not alter the PK of tenofovir. The administration of ddI simultaneously with tenofovir and a light meal results in an elevated ddI exposure, suggesting that it is possible to administer ddI and tenofovir together with a light meal and that a reduction in ddI dosage is necessary.

Clinical Implications

Unfortunately, no dosing alteration of ddI was suggested in this study, and further studies are ongoing. However, it appears that the administration of tenofovir and ddI is possible without reduction in ddI exposure if given together with a light meal. However, how they define "light meal" was not mentioned in the abstract. Whether "heavier" meals may alter the PK differently is therefore unclear. However, in the light of this data, many physicians have decided to reduce the dose of ddI to 250 mg in patients where tenofovir and ddI are administered within the same antiviral regimen.

Certainly at our unit at Chelsea and Westminster Hospital in London this has been common practice. We have not observed an increase in adverse events, and many patients have commented that minor ddI-related adverse events such as dry mouth, have either disappeared or been reduced by this dosing strategy. Some authors have suggested that even with the reduction to 250 mg there may still be a cause for greater ddI exposure and therefore more severe toxicities such as pancreatitis. This has not been observed at our unit.

The other advantage of this dosing strategy is that tenofovir, ddI and other once-daily drugs may be given as true once-daily therapy. Many patients have also commented on the relative ease of administration of such a regimen compared with when ddI was dosed with food restriction. Further studies are ongoing looking at different doses of ddI with tenofovir with food, and physicians and patients need to make their own decisions regarding the relative risk of dosing these drugs together as against the probable efficacy of such a regimen and ease of administration.