Pharmacokinetic evaluation of tenofovir and enteric-coated ddI
1 February 2003. Related: Conference reports, Antiretrovirals, PK and drug interactions, HIV 6th Glasgow 2002.
Mark Nelson, TheBody.com
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. TDF has been increasingly used in antiretroviral therapy following the results of study 903. This study looked at the regimen of TDF/3TC (lamivudine, Epivir)/efavirenz (EFV, Sustiva), and, at 48 weeks, more than 85% of study participants were able to reach a viral load below 400 copies.
Didnosine 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 (ie exposure) is reduced by approximately 25% when taken with food.
However, previous evidence has suggested that when TDF 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 TDF, 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 TDF/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/TDF 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 enteric coated ddI together with TDF either in the fasting state or with a light meal made no difference to the TDF PK. However, in individuals where ddI was administered at the full dose of 400 mg with a light meal, together with TDF, 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 (ie 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 of TDF and ddI with a light meal did not alter the PK of TDF. The administration of ddI simultaneously with TDF and a light meal results in an elevated ddI exposure, suggesting that it is possible to administer ddI and TDF 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 TDF 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 TDF 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 TDF, 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 TDF 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.
Reference:
B.P. Kearney. Tenofovir DF (TDF) and Didanosine EC (ddI EC): Investigation of Pharmacokinetic (PK) Drug-Drug and Drug-Food Interactions. Poster 932, The 6th International Congress on Drug Therapy in HIV Infection
Source: The Body
© 2002 Body Health Resources Corporation.