Determination of Dissolution Profile and Bioaccessibility of Ketosteril Using an Advanced Gastrointestinal In Vitro Model

Abstract

Ketosteril is an originator drug prescribed for nutrition therapy for patients with chronic kidney disease (CKD). Ketoanalogues (KAs) of amino acids are part of the active pharmaceutical ingredients in the Ketosteril film-coated tablets. The in vitro dissolution and gastrointestinal (GI) release of KAs available in Ketosteril were determined in this study using a dynamic multi-compartmental system, TIM-1. A water-fed mode of operation for TIM-1 was used to study the dissolution and bioaccessibility of KA during an experimental 5-hour test. Overall recovery (i.e., mass balance) and bioaccessibility as a function of time were the major outcome parameters. Based on eight experimental runs, the mean ± SD percent recovery was 95.2 ± 4.0 (RSD: 4.2), showing high reproducibility for the dissolution of a solid dosage form in a highly complex in vitro model. The bioaccessible fraction (BioAcc) of KA was found to be highest at 2 and 3 hours. Furthermore, the total BioAcc was found to be higher for the jejunum (68.2%-68.7% of dosage) than the ileum (15.9%-17.9% of dosage). The in vitro results of this study show that the release of Ketosteril KAs occurs at physiological relevant sites, mainly the jejunum, with its amino acid receptor for absorption, as it has been reported in clinical observations with humans. These bioaccessibility results may explain the clinical performance of Ketosteril reported in several clinical trials of patients with CKD with regards to postponing dialysis. Ketosteril in combination with a low protein diet has been proved to be a nutritionally safe therapy.

Results from a Validated in vitro Gastrointestinal Model (TIM) used as input Data for in silico Modeling Give Highly Predictive Information for the Human Situation

“…In a pharma study by Brito-de la Fuente et al ketosteril film-coated tablets were tested in eight experimental runs in TIM-1. 36 The GI conditions of patients with chronic kidney disease (CKD) were simulated under fasted conditions. The release, dissolution and bioaccessibility of ketoanalogues of amino acids from ketosteril were evaluated.…”