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How GSK Used Biorelevant Media

How GlaxoSmithKline (GSK) used Biorelevant Media (FaSSIF, FeSSIF and FaSSGF) to improve the solubility and dissolution of their novel drug danirixin for improved bioavailability.

What problem was the team at GSK facing?
The free base form of danirixin, a novel drug being investigated as an influenza treatment, was variable in terms of its performance due to the differences in stomach pH of patients. This was especially the case with patients taking proton pump inhibitors (PPIs) which increase the pH of the stomach approximately from pH 2 to pH 4. Increased stomach pH means more variable drug performance for basic compounds resulting in lower drug solubility in the small intestine.

What strategy did GSK take to identify a salt form of danirixin with improved bioavailability?
First of all, the team at GlaxoSmithKline carried out a salt screen to identify a salt form with improved water solubility compared to the free base form. Then the solubility of the danirixin free base form and the salt form in Biorelevant Media (FaSSIF and FeSSIF) was measured. Dissolution testing of both formulated danirixin dosage forms in different media was also performed. Finally a Phase 1 clinical trial was carried out confirming the improvement in human performance of the salt form of danirixin.

How did Biorelevant Media help?
According to Bloomer et al.: “Measured particle size, pH versus solubility data and solubility in Biorelevant Media (FaSSGF, FaSSIF and FeSSIF) gave an accurate prediction of how the solubility of the API varies as the pH and level of surfactants varies in the gastrointestinal tract in the fasted and fed states”. This solubility data, together with dissolution testing in FaSSIF, was key in determining the superior performance of the salt form of danirixin versus the free base form.

The take-home message
Biorelevant Media showed that the salt form of danirixin has improved solubility and an excellent dissolution profile compared to the free base form which in vivo translated to improved bioavailability. This was especially the case for patients taking PPIs which increase gastric pH.

Reference:
1. Bloomer, J. C. et al. Identification and characterisation of a salt form of Danirixin with reduced pharmacokinetic variability in patient populations. Eur. J. Pharm. Biopharm. 117, 224–231 (2017).

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