Effect of Food on the Oral Bioavailability of Didanosine from Encapsulated Enteric-Coated Beads

Abstract

The objective of this study was to assess the effect of food and timing of meals on the bioavailability of didanosine from encapsulated enteric-coated beads. Four different independent, open-label, single-dose, randomized, crossover studies were conducted in healthy subjects (n = 20-30). Didanosine (400 mg) was given concomitantly with a high-fat meal, light meal, yogurt, and applesauce. In addition, didanosine was given 1, 1.5, 2, and 3 hours before and 2 hours after a light meal. Statistical comparison with fasting conditions was made using the equivalence approach for Cmax (70%-143%) and AUC (80%-125%). The high-fat meal, light meal, yogurt, and applesauce decreased the Cmax by 46%, 22%, 30%, and 24%, respectively, and lowered the AUC by 19%, 27%, 20%, and 18%, respectively; statistical analyses indicated an indeterminate food effect, except for the Cmax for the high-fat meal. For 1 hour before meal, Cmax and AUC were lower by 15% and 24% and, for 2 hours after meal, were lower by 15% and 10%, respectively. There was an indeterminate food effect for 1 hour before the meal treatment; in addition, 2 hours after the meal, treatment approached statistical equivalence, missing narrowly on the lower bounds. For 1.5, 2, and 3 hours before meal treatments, Cmax values were unchanged, but AUC was lower by 10%, 4%, and 0%, respectively; lack of food effect was observed for all three treatments. Across studies, median time to Cmix ranged from 1.67 to 2.67 hours but was delayed by 2.5 to 3 hours with high-fat and light meals compared to fasting conditions. The half-life of didanosine was 1.5 to 2 hours. It was concluded that the bioavailability of didanosine from encapsulated enteric-coated beads was reduced by approximately 20% to 25% with food, which can be circumvented by taking didanosine on an empty stomach. The clinical significance of such moderate reductions in didanosine exposure with food, especially as part of a highly active antiretroviral therapy, is not clear.

Clinical Relevance of Drug Interactions in HIV-Infected Patients Receiving Antiretroviral Therapy

“…For example, in the case of didanosine (buffered tablet and enteric-coated granules within capsules), it is recommended to take it on an empty stomach (2 hours before or two hours after meals), (la Porte et al, 2005) because a decrease (between 18 and 55%) in the amount absorbed can be produced (level 3: risk medium). (Damle et al, 2002c;Kearney et al, 2005) Such effect may be minimized if didanosine is administered in combination with indinavir/ritonavir or with tenofovir (La Porte et al, 2005;Kearney et al, 2005) (see didanosine-tenofovir Interaction below).…”

Understanding the mechanism of drug delivery from thickened fluids to aid swallowing of medications

“…Crushed medications can be dispersed, sprinkled or mixed with water or other fluid vehicles such as apple sauce, jam, custard, yoghurt, honey, juice or thickened fluids (Nissen et al, 2009, Lee et al, 1996, Gidal et al, 1998, McLean et al, 2001, Fay et al, 2005, Jann et al, 1986, Damle et al, 2002.…”

“…two tablespoons) of food such as pudding, yoghurt or apple sauce usually does not significantly alter bioavailability (Lee et al, 1996, Gidal et al, 1998, McLean et al, 2001, Damle et al, 2002. However, certain foods are known to affect drug absorption, for example a component in fruit juice such as grapefruit, orange and apple juice affects absorption of numerous medicines (Bailey, 2010, Jeon et al, 2013, Lilja et al, 2005 and fibre products ingested with the medication affect gastric emptying (Damle et al, 2002, Huupponen et al, 1984. Furthermore, mixing crushed phenytoin tablets with pudding resulted in impaired absorption in comparison to the use of apple sauce (Jann et al, 1986).…”

“…14 Enteric-coated beads of didanosine administered with yoghurt or apple sauce delayed absorption (Damle et al, 2002) and coadministration of quinolones with yogurt decreased absorption and bioavailability due to formation of insoluble drug-calcium complex (Neuhofel et al, 2002). In another study, milk reduced absorption of oseltamivir due to direct interaction with the proton coupled oligopeptide transporter (PEPT1) (Morimoto et al, 2011).…”

“…In Australia, medications were altered before being given to the patient in 34% of 408 observations in aged care facilities (Paradiso et al, 2002), and nurses at 79% of 97 health facilities altered medicines to ease administration (Nissen et al, 2009). This commonly involves crushing tablets or opening capsules and mixing the contents into food or fluids such as apple sauce, jam, custard, yoghurt, honey or juice (Nissen et al, 2009, Lee et al, 1996, Gidal et al, 1998, McLean et al, 2001, Fay et al, 2005, Jann et al, 1986, Damle et al, 2002. Patients suffering from dysphagia often have their fluid and dietary intake managed by the use of thickening agents in order to ensure safe swallowing and avoid aspiration into the airway (Jukes et al, 2012).…”