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From FDA: How to conduct DDI studies with acid-reducing drugs

Posted 02 December 2020 | By Kari Oakes 

From FDA: How to conduct DDI studies with acid-reducing drugs

A new draft guidance from the US Food and Drug Administration (FDA) addresses how to conduct drug-drug interaction studies with acid-reducing medicines that can make the gastric environment more alkaline. 
 
Medicines such as proton pump inhibitors and histamine H2 receptor antagonists, dubbed acid-reducing agents or ARAs, are in wide use and many are available without a prescription. “ARAs can affect the solubility and dissolution characteristics of orally administered drug products by elevating gastric pH,” noted FDA’s Office of Clinical Pharmacology (OCP) in announcing the availability of the draft guidance for industry.
 
The FDA announcement noted that “concomitant administration of a drug with an ARA could alter the bioavailability of the drug, potentially resulting in a loss of efficacy for weak-base drugs or increased adverse events for weak-acid drugs.” The new document offers proposed guidance for assessing how susceptible an investigational drug is to gastric pH-mediated drug-drug interactions (DDIs) that may be clinically significant.
 
When a drug is under development, especially if the indicated population is likely to be taking ARAs, clinical DDI studies with ARAS should be considered for immediate-release formulation of weak-base and weak-acid drugs.
 
FDA provides an algorithm to evaluate clinical DDI risk for weak-base drugs that takes into account pH-dependent solubility within the pH range of the gastric milieu as well as drug soubility and dissolution profiles in different media conditions. Measures captured should include solubility and the formulation and dose to be used in a dissolution test. For medicines intended to be taken with food, the fed-state pH should also be taken into consideration; “in vitro testing results might not be predictive of pH-mediated DDI under the fed condition,” according to the guidance.
 
“There is limited experience with weak-acid drugs,” but in general pH-dependent DDIS for weak-acid drugs are “generally modest,” notes the guidance, so the safety profile of the investigational drug will dictate the need for in vivo study.
 
Extended- and delayed-release products can also have DDIs with ARAs if the mechanism for the modified release time is pH-sensitive. Here also, data are “very limited,” so FDA encourages sponsors to contact the appropriate review division for assistance in determining whether DDI studies are needed.
 
For clinical DDI studies, standalone studies with healthy subjects will generally suffice, barring undue risk to healthy participants as would occur with cytotoxic drugs. Crossover design is preferred, but a parallel design might make sense for drugs with long half-lives, according to the guidance. Single-dose administration of the investigational drug will generally suffice.
 
The pharmacodynamic characteristics of individual ARAs should be taken into consideration when choosing the ARA and designing the study. FDA gives particulars to consider for each ARA in the guidance.
 
“To characterize the worst-case scenario, the sponsor should select the maximum recommended dose of an ARA,” notes FDA. Likewise, the maximum dose of an investigational drug that would be given for therapeutic purposes should also be used.
 
Pharmacokinetic sampling should be timed to capture all pharmacokinetic characteristics of the investigational drug administered both alone and with an ARA. If the drug has active metabolites that play into either efficacy or safety, those should also undergo pharmacokinetic analysis.
 
The draft guidance also offers alternative approaches such as population pharmacokinetic analysis and physiologically based pharmacokinetic simulations.
 
Clinical DDI results can generally be extrapolated to other DDIs within the same class, unless there are also non-gastric pH-related DDIs between the ARA and the investigational drug.
 
“PPIs represent a worst-case scenario for pH-dependent DDIs due to their long-lasting effects on gastric pH,” writes FDA in the draft guidance. “Thus, a negative result from a dedicated study with a PPI indicates the lack of a pH-dependent DDI for an investigational drug.”
 
The guidance walks sponsors through labeling implications for each class of ARA when a PPI-based study shows a clinically significant change in drug exposure. Appended to the guidance is a flow chart clarifying labeling options, or the alternative to conduct further study with individual classes of ARAs.
 
The draft guidance is available for public consultation for 90 days from the date of publication in the Federal Register.
 
FDA
 

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