ADMET and DMPK (Oct 2020)

Global testing of a consensus solubility assessment to enhance robustness of the WHO biopharmaceutical classification system

  • Valeria Gigante,
  • Giovanni M. Pauletti,
  • Sabine Kopp,
  • Minghze Xu,
  • Isabel Gonzalez-Alvarez,
  • Virginia Merino,
  • Michelle P. McIntosh,
  • Anita Wessels,
  • Beom-Jin Lee,
  • Kênnia Rocha Rezende,
  • Gerhard K.E. Scriba,
  • Gaurav P. S. Jadaun,
  • Marival Bermejo

DOI
https://doi.org/10.5599/admet.850

Abstract

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The WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to engage a global network of laboratories to experimentally quantify the pH-dependent solubility of the highest therapeutic dose of 16 APIs using a harmonized protocol. Intra-laboratory variability was ≤5 %, and no apparent association of inter-laboratory variability with API solubility was discovered. Final classification “low solubility” vs “high solubility” was consistent among laboratories. In comparison to the literature-based provisional 2006 WHO BCS classification, three compounds were re-classified from “high” to “low-solubility”. To estimate the consequences of these experimental solubility results on BCS classification, dose-adjusted in silico predictions of the fraction absorbed in humans were performed using GastroPlus®. Further expansion of these experimental efforts to qualified APIs from the WHO Essential Medicines List is anticipated to empower regulatory authorities across the globe to issue scientifically-supported guidance regarding the necessity of performing in vivo bioequivalence studies. Ultimately, this will improve access to affordable generic products, which is a critical prerequisite to reach Universal Health Coverage.