Novartis, Merck, GlaxoSmithKline (GSK), Gilead, Bayer, AstraZeneca, AbbVie and Takeda offered their opinions on recent FDA draft guidance on potential drug-drug interactions (DDIs) with pH modulating agents such as proton-pump inhibitors (PPI) or acid reducing agents (ARA).
The comments follow the release of draft guidance in May
that explains how for a drug whose solubility is pH-dependent, concomitant administration with an ARA “may affect its absorption and systemic exposure, potentially resulting in loss of efficacy or, in some cases, increased toxicity.”
Laying out the need for such a guidance, Gilead notes, “Antacids, histamine H2-receptor antagonists (H2 blockers), and proton pump inhibitors (PPIs) are widely used, and many of these products are available over the counter… it is important to assess a drug's susceptibility to pH-dependent DDIs during drug development, characterize the DDI effect with clinical studies when needed, and communicate study results in the drug labeling.”
Gilead, like most of the other commenters, lays out a stepwise approach (though Gilead’s is five steps and most of the others are longer) for determining the characteristics of drugs that are susceptible to pH-dependent DDIs.
“In general, modeling efforts should be employed to extrapolate to other ARAs and reduce unnecessary clinical DDI studies. Results from adequate modeling approaches should be sufficient to inform label recommendations,” Gilead said.
Takeda Pharmaceuticals added that the “ability to predict interactions with either a top-down or bottom-up approach may depend on the type of data available (in vitro, PK, PD), understanding of the interaction mechanism, and how confidently we can quantify the extent of the interaction in vivo based on in vitro or animal data where applicable.”
Merck, meanwhile, emphasized “that, in our experience, pH-dependent solubility in itself does not necessarily lead to a pH-dependent DDI.”
“If the dose/solubility ratio in the intestine is not very high (even if it’s outside BCS I/III bounds), solubilization in the intestine can be sufficient to lead to equivalent absorption regardless of stomach pH. Formulation approaches, including use of acidulants in the formulation or use of amorphous solid dispersions, may also mitigate the pH-interaction by improving the dissolution rates regardless of pH,” Merck said.
Bayer, meanwhile, calls on the agency to consider addressing “absorption-mediated drug-drug interactions.”
“Due to the complex interplay between altered physico-chemical (i.e. pH dependent solubility), galenical (type of formulation) and physiological factors (e.g. gastric pH, gastrointestinal-motility) the extent to which DDI may impact bioavailability can vary substantially,” Bayer said.
In addition, AstraZeneca proposes that the decision making and guidance “should be based on a ‘totality of data’ foundation and a growing knowledge of IVIVC [in-vitro in-vivo correlation] which includes: physicochemical properties of the drug candidate, dissolution/formulation properties, nonclinical pharmacology, principles of PBPK, clinical pharmacology, and clinical trial data.”
AbbVie also digs in on the extrapolation of findings from one ARA to another, explaining factors to help guide extrapolation and noting that extrapolation “is important as it can have implications on labeling recommendations.”
GSK also noted that it “should be possible to extrapolate the pH related impact for all acid modifying agents where the extent and duration of the modification to gastric secretion/gastric pH is understood, as this driven by a physicochemical mechanism common to all.”