An Investigation into the Influence of Experimental Conditions on In Vitro Drug Release from Immediate-Release Tablets of Levothyroxine Sodium and Its Relation to Oral Bioavailability

The aim of this study was to investigate the influence of experimental conditions on levothyroxine sodium release from two immediate-release tablet formulations which narrowly passed the standard requirements for bioequivalence studies. The in vivo study was conducted as randomised, single-dose, two-way cross-over pharmacokinetic study in 24 healthy subjects. The in vitro study was performed using various dissolution media, and obtained dissolution profiles were compared using the similarity factor value. Drug solubility in different media was also determined. The in vivo results showed narrowly passing bioequivalence. Considering that levothyroxine sodium is classified as Class III drug according to the Biopharmaceutics Classification System, drug bioavailability will be less sensitive to the variation in its dissolution characteristics and it can be assumed that the differences observed in vitro in some of investigated media probably do not have significant influence on the absorption process, as long as rapid and complete dissolution exists. The study results indicate that the current regulatory criteria for the value of similarity factor in comparative dissolution testing, as well as request for very rapid dissolution (more than 85% of drug dissolved in 15 min), are very restricted for immediate-release dosage forms containing highly soluble drug substance and need further investigation. The obtained results also add to the existing debate on the appropriateness of the current bioequivalence standards for levothyroxine sodium products

Justification of metformin hydrochloride biowaiver criteria based on bioequivalence study

The Biopharmaceutics Classification System (BCS) represents the framework for predicting the intestinal drug absorption based on its solubility and intestinal permeability. Recent research has lead to the use of in vitro tests to waive additional in vivo bioequivalence studies for some pharmaceutical products (i.e. biowaiver). The current regulations permit waivers for BCS Class I (highly soluble/highly permeable) drug substances, which represent up to 25% of the drugs. Efforts in both the science and regulatory bodies are being made to extend biowaivers to certain Class II and III products, which would represent more than 50% of all drugs coming to the market. The aim of this study was to investigate the influence of experimental conditions on metformin hydrochloride (CAS 1115-70-4) release from two immediate-release tablet formulations with proven bioequivalence and justify the biowaiver request for dissolution profile similarity in three pH media. The results obtained indicate that differences in drug dissolution observed in vitro were not reflected in vivo. Such data support the existing idea that BCS Class III drugs are eligible biowaiver candidates, even if a very rapid dissolution criterion is not fulfilled

A case study on the in silico absorption simulations of levothyroxine sodium immediate-release tablets

The aim of this case study was to develop a drug-specific absorption model for levothyroxine (LT4) using mechanistic gastrointestinal simulation technology (GIST) implemented in the GastroPlus (TM) software package. The required input parameters were determined experimentally, in silico predicted and/or taken from the literature. The simulated plasma profile was similar and in a good agreement with the data observed in the in vivo bioequivalence study, indicating that the GIST model gave an accurate prediction of LT4 oral absorption. Additionally, plasma concentrationtime profiles were simulated based on a set of experimental and virtual in vitro dissolution data in order to estimate the influence of different in vitro drug dissolution kinetics on the simulated plasma profiles and to identify biorelevant dissolution specification for LT4 immediate-release (IR) tablets. A set of experimental and virtual in vitro data was also used for correlation purposes. In vitroin vivo correlation model based on the convolution approach was applied in order to assess the relationship between the in vitro and in vivo data. The obtained results suggest that dissolution specification of more than 85% LT4 dissolved in 60 min might be considered as biorelevant dissolution specification criteria for LT4 IR tablets. Copyrigh