Bioequivalence of Two Formulations of Didanosine, Encapsulated Enteric‐Coated Beads and Buffered Tablet, in Healthy Volunteers and HIV‐Infected Subjects

Abstract

Didanosine is an acid labile drug and hence has been given with buffering agents. To avoid the need for concurrent administration with antacids, an encapsulated enteric-coated bead formulation of didanosine was developed. The objective of this study was to assess the bioequivalence of the encapsulated enteric-coated beads compared to the buffered tablet. Two separate open-label, randomized, two-way crossover studies were conducted, one in healthy subjects and the other in HIV-infected subjects (with CD4 cell counts > 200 cells/mm3). All subjects received a 400-mg dose of the buffered tablet (reference formulation) and the encapsulated enteric-coated beads (test formulation). Blood samples were collected over 12 hours, and plasma levels of didanosine were determined using a validated assay. The 90% confidence interval (CI) of the ratio of the geometric means of log-transformed Cmax and AUCinfinity values were used to assess bioequivalence between the two formulations using the equivalence interval of 0.80 and 1.25. In healthy volunteers (n = 46), the point estimate and 90% CI of the ratios of Cmax and AUCinfinity values were 0.58 (0.52, 0.64) and 1.02 (0.95, 1.01), respectively. In HIV-infected subjects (n = 30), the point estimate and 90% CI of the ratios of Cmax and AUCinfinity values were 0.64 (0.56, 0.72) and 0.95 (0.86, 1.06), respectively. Median t(max) value increased significantly from 0.67 hours for the buffered tablet in both studies to 2.33 hours (in healthy subjects) or 2.0 hours (in HIV-infected subjects) for the enteric-coated beads. The mean half-life of didanosine was similar between treatments and ranged between 1.60 and 1.70 hours across healthy and HIV-infected subjects. It was concluded that the encapsulated enteric-coated bead formulation of didanosine is equivalent to the buffered tablet in the extent of exposure but differs in the rate of absorption. The pharmacokinetic profile of the enteric formulation appears to be similar in healthy and HIV-infected subjects.

Selection and Characterization of Suitable Lipid Excipients for use in the Manufacture of Didanosine-Loaded Solid Lipid Nanoparticles and Nanostructured Lipid Carriers

“…4,5 A major hindrance to the use of DDI is the susceptibility of the molecule to hydrolytic cleavage in the acidic environment of the stomach, following oral administration with conventional formulations. 3,6 In reality, DDI has a t 90 of less than 2 min in a solution of pH 3.0 at 37 • C. 3,7 Consequently, there is a reduction in the bioavailability and in vivo activity of the molecule. 3,6,8 In order to improve the acid stability and bioavailability of DDI, the drug is usually formulated as buffered chewable or dispersible tablets in addition to buffered or nonbuffered pediatric powders for reconstitution as an oral solution.…”

“…3,6 In reality, DDI has a t 90 of less than 2 min in a solution of pH 3.0 at 37 • C. 3,7 Consequently, there is a reduction in the bioavailability and in vivo activity of the molecule. 3,6,8 In order to improve the acid stability and bioavailability of DDI, the drug is usually formulated as buffered chewable or dispersible tablets in addition to buffered or nonbuffered pediatric powders for reconstitution as an oral solution. 3,6,8,9 The nonbuffered pediatric powders are usually mixed with antacids following reconstitution, prior to oral administration to pediatric patients.…”

“…3,6,8 In order to improve the acid stability and bioavailability of DDI, the drug is usually formulated as buffered chewable or dispersible tablets in addition to buffered or nonbuffered pediatric powders for reconstitution as an oral solution. 3,6,8,9 The nonbuffered pediatric powders are usually mixed with antacids following reconstitution, prior to oral administration to pediatric patients. 10 Despite these formulation strategies, the bioavailability of DDI in children with HIV infection remains highly variable and may range between 13% and 29%.…”

“…10 Despite these formulation strategies, the bioavailability of DDI in children with HIV infection remains highly variable and may range between 13% and 29%. 5,11 Furthermore, DDI-buffered formulations are unpalatable 6,9 and the presence of buffers and/or antacids in these formulations have been reported to cause diarrhoea, nausea, vomiting, 6,9 and abdominal discomfort. 4,5,9 The presentation of these side effects in addition to pancreatitis and peripheral neuropathy, which can be directly attributed to DDI, 4,5 may have a negative outcome on the quality of life of pediatric patients.…”

Oral modified-release formulations in motion: The relationship between gastrointestinal transit and drug absorption

“…In the case of didanosine, for example, enteric-coated beads (Videx ® ) have shown a lower variability in bioavailability compared to enteric-coated tablets and a faster onset of absorption (shorter t max ). This information led to the clinical development and subsequent commercialization of the didanosine enteric-coated granule preparation and the discontinuation of the enteric-coated tablet formulation (Damle et al, 2002a, Damle et al, 2002b. However, when food is introduced into the dosing scenario, the results can become more complex.…”