The new capsule formulation of ddI, known as Videx EC, has run into unexpected problems over the dosing schedule after the Swedish drug licensing authority expressed concern over data that showed a reduction in total drug exposure in those who take Videx EC with or after food. This decision affects the whole of the European Union.
Manufacturer Bristol Myers Squibb had assumed that licensing authorities would approve the new formulation on the same dosing schedule as the tablet formulation - half an hour before food and/or two hours after. Patients receiving Videx EC through the named patient access scheme had been advised by pharmacies that the old rules applied, and the sudden change has caused considerable confusion.
What does the data show?
An equivalence study of the old and new formulations taken once daily shows no significant difference in the proportion of patients with undetectable viral load after 24 weeks on a triple combination which included ddI. Studies have already demonstrated equivalent effect on viral load over 12 weeks of follow-up when once daily and twice daily dosing of ddI tablets (old formulation) are compared.
However, a study of plasma levels in healthy volunteers showed a significant reduction in total drug exposure if Videx EC was taken with a light meal (-27%), 1 hour before (-24%) or 2 hours after a meal (-10%), compared to taking it on an empty stomach, but the clinical significance of this reduction was not known at the pre-licensing stage because equivalence studies showed no difference in efficacy between the old and new formulations.
After reviewing the data, the Swedish licensing authority advised that in the absence of any evidence to the contrary, it would be safer to assume that a reduction in total drug exposure may be clinically relevant, and they recommended that Videx EC should be taken at least two hours after eating.
In the UK the HIV Pharmacy Association has gone even further than the Swedish licensing authority, and has advised in a factsheet for distribution to patients that the drug should be taken at least two hours before eating and/or two hours after eating. This means a longer delay before eating than experienced when taking the ddI tablet, which must be taken at least half an hour before eating.
The difference is due to the speed at which the drug from the Videx EC capsule is absorbed; ddI levels in the blood take 40 minutes to reach their peak if you take the tablet formulation, but around two hours if you take the capsule. This is because the new formulation takes longer to break down and pass from the stomach.
Effectively, the findings mean that the drug is probably best taken at bedtime - provided that you haven't eaten anything (or drunk anything part from water) for at least two hours beforehand.
Further change in dosing advice is possible, warns BMS
This isn't the end of the story, however. Bristol Myers Squibb will now be looking at data from a variety of studies in order to determine the dosing schedule more precisely, and further dosing clarification may occur during 2001 if there is any evidence to support such changes.