Danazol oral absorption modelling in the fasted dog: An example of mechanistic understanding of formulation effects on drug pharmacokinetics

Devendra Pade, Masoud Jamei, David B. Turner, Bipin Mistry, Marilyn N. Martinez
In: European Journal of Pharmaceutics and Biopharmaceutics · 2019 · vol. 141 , pp. 191–209 · doi:10.1016/j.ejpb.2019.05.024 · PMID:31150808 · W2947444671
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This study developed a mechanistic model to describe danazol oral absorption in fasted dogs, demonstrating how formulation characteristics influence drug pharmacokinetics.

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Abstract

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies. In this work, we detail the development and application of the Simcyp canine ADAM model to nine danazol oral formulations and compare the model predictions to caninein vivo pharmacokinetic data from published literature. The application of this mechanistic approach revealed insights suggesting: (1) complete danazol solubilization in vitro may lead to an over-estimation of oral bioavailability when predictions are not corrected for the in vivo conditions promoting gut luminal precipitation; (2) some solubilizing excipients can influence intestinal physiology in a manner that may reduce danazol absorption; (3) danazol-formulation-luminal bile salts interplay can result in the formation of mixed micelles that negatively impact danazol intestinal permeability; and (4) the magnitude of danazol bioavailability enhancement associated with the use of solubilizing agents can be affected by the presence of saturable gut metabolism that can lead to concentration-dependent differences in its influence in vivo formulation behaviour at high versus low doses.

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