Track: Formulation and Delivery - Chemical - Drug Delivery - Other
Category: Poster Abstract
Assessing the Pharmacokinetics and Biodistribution of Amphotericin B following Oral Administration of Three Novel Oral Amphotericin B Formulations to Beagle Dogs
Purpose: The purpose of this study was to determine the pharmacokinetics of amphotericin B following a single oral dose of 100 mg (~10 mg/kg) in either in liquid formulation (iCo-010) or from two capsule formulations of amphotericin B (iCo-019 and iCo-022) and the tissue distribution of amphotericin B 24 hours following three days of a single oral dose (10 mg/kg) per day dosing of the capsule formulations of amphotericin B in Beagle dogs. Methods: The liquid formulation of amphotericin B (iCo-010; 10 mg/kg single dose) was administered to three male dogs and the capsule formulations of amphotericin B iCo-019 and iCo-022 (10 mg/kg single dose) were administered to each of two groups of six male dogs. Blood was collected for pharmacokinetic evaluation on Day 1, 2 and 3 (up to 72 hours post-dosing). Dogs receiving the capsule formulations further received a single oral dose of 10 mg/kg once daily for three more days and on the fourth day blood samples were taken 24 hours post-dosing and the dogs were humanely sacrificed with the removal of the following organs from which tissue samples were taken for analysis of amphotericin B content: Brain (cerebrum, cerebellum, medulla), heart, kidney (cortex and medulla), liver, lung, spleen, testes, mesenteric lymph node and gastrointestinal tract sections (duodenum, jejunum, ileum and colon). A sample of intestinal contents was also collected. Amphotericin B plasma and tissue concentrations were determined by a validated LC-MS assay and pharmacokinetic non-compartmental analysis was completed using WInNonLin. Tolerability of the formulations within each dog was assessed by measuring changes in body weight, food and water intake, and by monitoring for any signs of gastrointestinal disturbances such as vomiting or diarrhea. Results: Oral administration of amphotericin B at a dose of 10 mg/kg (100 mg dose) was well tolerated in dogs in all the formulations that were tested and there were no relevant adverse clinical signs observed such as loss of weight, changes in food or water intake or signs of gastrointestinal distress (i.e. vomiting or diarrhea).
Following oral dosing with iCo-010 (Figure 1), iCo-019 and iCo-022 their mean Cmax, Tmax and AUC0-Tlast values were not significantly different from each other (Table 1).
The range of Cmax, Tmax, and AUC0-Tlast for iCo-010, iCo-019 and iCo-022 ranged from 53.2 - 62.3, 24.9 - 66.4 and 36.7 - 85.2 ng/ml (Cmax); 4 - 12, 4- 24 and 2 -24 hours (Tmax); and 2635 - 3071, 1053 - 2517 and 1443 - 3713 ng-hr/mL (AUC0-Tlast), respectively. Mean MRTLast and mean plasma t1/2 for iCo-10, iCo-019, iCo-022 were not significantly different from each other ranging from 31.1 - 32.3, 25.3 - 28.7 and 22.2 - 32.8 hours (MRTLast) respectively and ranging from 25.9 to 58.4 hours (t1/2).
The tissue distribution and intestinal contents of amphotericin B were similar following repeated doses of the two capsule formulations iCo-019 and iCo-022 to dogs. Gastrointestinal tissues and contents contained the highest levels with intestinal content levels ranging from 1938.8 - 3106.6 ng/g w.w. Among non-gastrointestinal tissues, the kidney cortex and medulla followed by the liver and mesenteric lymph node had the highest tissue levels ranging from 21.7 - 157.8 ng/g w.w. The remaining tissues had very low levels of amphotericin B with tissue levels ranging from 0.0 - 7.6 ng/g w.w. Conclusion: In conclusion, oral dosing of amphotericin B at a dose of 100 mg (~ 10 mg/kg) was well tolerated in dogs with all formulations (iCo-010, iCo-019 and iCo-022) tested. The oral absorption of amphotericin B from iCo-010 liquid formulation and iCo-019 and iCo-022 capsule formulations were similar with no significant differences between the formulation groups for Cmax, Tmax, and AUC0-Tlast. The tissue distribution of amphotericin B following dosing with iCo-019 and iCo-022 was similar, with the highest levels found in gastrointestinal tissues, followed by the kidney, liver and mesenteric lymph node, lower levels observed in the lung, spleen and testis, and very low levels observed in regions of the brain and heart.