A Systematic Review of Gastric Acid-Reducing Agent-Mediated Drug–Drug Interactions with Orally Administered Medications

Abstract

Background and Objective Several review articles have been published discussing gastric acid-related drug-drug interactions (DDIs) mediated by coadministration of antacids, histamine H 2 receptor antagonists, or proton pump inhibitors, but are not sufficiently comprehensive in capturing all documented DDIs with acid-reducing agents (ARAs) and tend to focus on gastric pH-dependent DDIs and/or basic drugs. Subsequently, several new drugs have been approved, and new information is available in the literature. The objective of this systematic review is to comprehensively identify oral medications that have clinically meaningful DDIs, including loss of efficacy or adverse effects, with gastric ARAs, and categorize these medications according to mechanism of interaction. Methods An indepth search of clinical data in the PDR3D: Reed Tech Navigator™ for Drug Labels, University of Washington Drug-Drug Interaction Database, DailyMed, Drugs@FDA.gov, and UpToDate ® /Lexicomp ® Drug and Drug Interaction screening tool was conducted from 1 June to 1 August 2018. The PDR3D, University of Washington Drug-Drug Interaction Database, and DailyMed were searched with terms associated with gastric acid and ARAs. Conflicting findings were further investigated using the UpToDate ® /Lexicomp ® screening tool. Clinical relevance was assessed on whether an intervention was needed, and prescribing information and/or literature supporting the DDI. Results Through the search strategy, 121 medications were found to clinically meaningfully interact with ARAs. For 38 medications the mechanism of interaction with ARAs was identified as gastric pH dependent, and for 83 medications the interaction was found to be not gastric pH mediated, with mechanisms involving metabolic enzymes, transporters, chelation, and urine alkalization. Additionally, 109 medications were studied and did not have a clinically meaningful interaction with ARAs. Conclusion This review may provide a resource to healthcare professionals in aiding the care of patients by increasing awareness of interactions with ARAs and may also identify and potentially aid in avoiding clinically relevant DDIs and preventing risk of treatment failure and/or adverse effects. Advances in non-clinical predictions of gastric pH-mediated DDIs may guide the need for a future clinical evaluation. Key PointsThis review provides an evaluation of the effectiveness and safety of currently available medicines when taken with medicines used to control stomach acid.

Bottom-Up Physiologically Based Oral Absorption Modeling of Free Weak Base Drugs

“…In the case of poorly soluble weak base drugs, gastric dissolution can have a marked impact on their oral absorption. Drug-drug interactions (DDI) with gastric acid-reducing agents (ARA), such as antacids, H 2 blockers, and proton pump inhibitors, are of great clinical importance, as they could reduce the efficacy of a drug by interfering with gastric dissolution [ 6 , 7 , 8 ]. In addition, elderly subjects tend to be achlorhydric [ 9 , 10 ].…”

Amorphous Solid Dispersion Tablets Overcome Acalabrutinib pH Effect in Dogs

“…Several weakly basic, oral oncologic drugs on the market have shown evidence of decreased absorption as a result of high gastric pH when taken with ARAs [ 26 , 27 ]. Weakly basic drugs made up 78% of new molecular entities approved between 2003 and 2013 that showed a clinical DDI with ARAs [ 4 ]. Since small-molecule protein kinase inhibitors are prevalent in pharmaceutical pipelines and many are poorly soluble, ASD dosage forms have the potential to enable effective delivery and improve the experience of many cancer patients [ 28 , 29 , 30 , 31 ].…”

“…Calquence has clinically meaningful drug–drug interactions (DDIs) with acid-reducing agents (ARAs) such as proton pump inhibitors (PPIs), where concomitant use results in reduced area under the plasma drug concentration–time curve (AUC) values [ 4 ]. For example, coadministration of Calquence with 40 mg of the PPI omeprazole for 5 days decreased AUC by 43% in healthy subjects [ 1 ].…”

“…The mechanism of reduced performance of acalabrutinib crystalline Form I when taken with ARAs is decreased solubility at the elevated gastric pH levels that occur when ARAs are administered, referred to here as the “ARA effect” [ 4 , 6 ]. The reduced solubility of the weakly basic drug decreases dissolution, which decreases absorption across the intestinal membrane and increases the extent of dose metabolized in humans [ 2 , 7 ].…”

“…This gastric pH-dependent mechanism that occurs with weakly basic drugs is the most common DDI for ARAs. However, natural variations in gastric pH also cause undesirable variability in Calquence performance, irrespective of the use of ARAs [ 4 , 8 , 9 , 10 ].…”