Intragastric pH and pressure profiles after intake of the high-caloric, high-fat meal as used for food effect studies.

Several review articles have been published discussing gastric acid-related drug–drug interactions (DDIs) mediated by coadministration of antacids, histamine H2 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. 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. 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. 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.

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

Effect of food and acid-reducing agents on the absorption of oral targeted therapies in solid tumors.

Poor aqueous solubility and dissolution of drug candidates drive key decisions on lead series optimization during drug discovery, on formulation optimization, and clinical studies planning during drug development. The interpretation of the in vivo relevance of early pharmaceutical profiling is often confounded by the multiple factors affecting oral systemic exposure. There is growing evidence that in vitro drug solubility may underestimate the true in vivo solubility and lead to drug misclassification. Based on 10 poorly water-soluble tyrosine kinase inhibitors, this paper demonstrates the use of physiologically-based pharmacokinetic (PK) analysis in combination with early clinical PK data to identify drugs whose absorption is truly limited by solubility in vivo and, therefore, expected to exhibit food effect. Our study supports a totality of evidence approach using early clinical data to guide decisions on conducting drug interaction studies with food and acid-reducing agents.

https://ascpt.onlinelibrary.wiley.com/doi/pdf/10.1002/cpt.1672

Evaluating the Role of Solubility in Oral Absorption of Poorly Water-Soluble Drugs Using Physiologically-Based Pharmacokinetic Modeling.

Proton pump inhibitors (PPIs) are the most commonly used anti-acid drugs worldwide, including among cancer patients. However, drug-drug interactions between PPIs and other agents may lead to decreased drug absorption with possible reduced therapeutic benefit, or even increased toxicity. Unfortunately, only scarce data exist regarding the safety of concomitant PPI use with anti-cancer agents. We aim at reviewing current evidence on this possible interaction by dividing anti-cancer agents by class. Until further data is available, we encourage healthcare providers to limit unnecessary PPI overuse.

Proton Pump Inhibitors and Oncologic Treatment Efficacy: A Practical Review of the Literature for Oncologists

The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.

Jane Holshouser

Papers

Effects of Esomeprazole on the Pharmacokinetics of Lapatinib in Breast Cancer Patients.