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HIGHLIGHTS OF 40th ICAAC: |
New Formulations of Existing Drugs for HIV
New Didanosine (Videx, ddI) ìEnteric Coatedî Formulation
There were three presentations about the new formulation (version) of didanosine (Videx, ddI), a nucleoside reverse transcriptase inhibitor (NRTI) drug. It will be called Videx-EC. The current formulation has ìbuffering agentsî that prevent the normal stomach acid from inactivating the drug. As a result, many other anti-HIV drugs may not be taken at the same time as didanosine. The buffering agents also contribute to some of the stomach-colon side effects of the drug. Bristol-Myers Squibb has developed a new formulation of didanosine that is ìenteric coated,î (protective coating) eliminating the need for added ìbuffers.î This allows for the ddI ìbeadletsî to pass through the stomach with the outer coating remaining intact. After entering the small intestine, the coating is dissolved and the drug is absorbed there into the bloodstream. The new formulation, to be taken once daily, was recently approved by the FDA.
There were two studies by Catherine Knupp, DVM comparing the new ìbeadletsî formulation of ddI to the currently available tablets. In the larger study, a total of 31 healthy (HIV negative) volunteers and 20 HIV positive persons were included. The HIV negative group included 34% women and 11% Blacks. The HIV positive group included 38% women, 41% Black and 25% Hispanic/Latino. The results showed that one 400 mg dose of each type led to the same total blood concentration (ìarea-under-the-curve,î ìAUCî) as the current buffered type. However, the peak or maximal concentration was decreased moderately when compared to the currently used type. This would not necessarily affect the drugís activity, since the active form is inside cells with 3 ìphosphateî groups added and since the ìAUCî concentration was the same. The level of ddI or ìddI-tri-phosphateî inside immune cells was not reported. Previous studies have shown that ìAUCî concentration of didanosine correlates with anti-HIV benefits. And, the authors note that the active form of ddI inside immune cells would likely be the same as with the current formulation, since the ddI active drug in both types is the same.
In the HIV positive patients, ìemergentî adverse events (side effects) occurred among 7% of those taking the beadlet formulation and 9% of those taking the standard formulation. The rates among the HIV negative volunteers were much higher: approximately 22%. Headache and nausea were the most common side effects. The authors concluded, ìThe absorption [into the blood] of didanosine fromÖenteric [formulated] encapsulated beadlets was equivalent to that from chewable/dispersible buffered tablet[s].î
In another presentation, the new Videx-EC was given with three other drugs to determine whether drug levels were affected. A total of 16-23 healthy volunteers (HIV negative) took one 400 mg dose of Videx-EC along with one dose of the following drugs: 800 mg of indinavir (Crixivan, protease inhibitor), 200 mg of ketoconazole (Nizoral, anti-fungal antibiotic) or 750 mg of ciprofloxacin (Cipro anti-bacterial antibiotic). The results were compared to each of the three drugs alone. Peak drug concentrations (maximum) and total concentration (ìarea-under-the-curveî or ìAUCî) of all four drugs were measured. The results showed near equal blood levels of the drugs in all comparisons. The minimum drug levels were not reported. However, the graphs on the poster indicated very little, if any change in the lowest concentrations of the drugs. Adverse events occurred in up to 23% of volunteers and resolved without any other treatment needed. The results suggest that either one of the three medications can be safely taken at the same time that Videx-EC is taken. It would have been helpful to have HIV positive patients included in the study. However, it might have been difficult to enroll such patients in this type of study. The presenting author was Vanaja Mummaneni, PhD of Bristol-Myers Squibb.