The gastric pH-dependent drug interactions with acid-reducing agents for oral oncology drugs current status and future assessment
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
The bioavailability of orally administered weak base drugs that exhibit pH-dependent solubility may be decreased when taken concomitantly with gastric acid reducing agents (ARAs), with potential to decrease the drug’s efficacy. The Food and Drug Administration (FDA) recently published a draft guidance for industry Evaluation of Gastric pH-Dependent Drug Interactions With Acid-Reducing Agents: Study Design, Data Analysis, and Clinical Implications. We have designed this study to assess how the guidance recommendations are implemented regarding: 1) when clinical drug-drug interaction (DDI) studies with acid-reducing agents (ARAs) are needed; 2) the design of clinical DDI studies; 3) how to interpret study results; and 4) communicating findings in drug product labeling with focus on oncology drugs. As the first step of this study, we have collected available data from FDA approved orally administered oncology new molecular entities (NMEs) which have data on co-administration with ARA treatment, including proton pump inhibitors (PPIs), H2-receptor antagonists (H2RAs), and local antacids. We have established a database with all NME NDAs reviewed for oncology indications and approved from 2008 to present, which includes pertinent information from the most recent FDA-approved label and relevant documents (e.g. the new drug application [NDA] submission, clinical pharmacology review, integrated quality review, etc.). Among the approved 94 oncology NME NDAs from 2008 to present, 77 were orally administered. Of which, 16 products (21%) do not exhibit pH-dependent solubility; 13 products (17%) have solubility at pH 6.0-6.8 greater than the value of clinical dose divided by 250 mL thus drug interaction with ARAs is unlikely; 38 products (49%) had dedicated DDI studies conducted with ARA(s), 8 products (10%) assessed the drug interaction with ARAs using PopPK and/or PBPK modelling approach, and 2 products (3%) evaluated the impact of co-administration with ARAs based on analysis of exposure and efficacy in patients in pivotal trials with the drug taken with or without gastric ARAs. Out of 38 products with dedicated clinical DDI studies conducted, the majority of products (30 out of 38, 79%) were studied with PPI only, 5 products (13.5%) were studied with a PPI and H2RA, 1 product (2.7%) was studied with a PPI and local antacid, 1 product (2.7%) was studied with a PPI, H2RA, and local antacid; and 1 product (2.7%) was studied with an H2RA only. Overall, 8 products (21%) have labeling recommendations regarding concomitant use of ARA therapy. Additionally, 8 products (22%) had DDI studies with ARA post approval with 1 study resulting in a labeling recommendation. Our next step of this study is to further analyze the data collected in the database to assess the differential effects of identified factors (e.g. solubility pH-dependency, food effect, bioavailability, etc.) on the clinical PK of oncology drugs that are prone to the interaction with ARAs. Additionally, we will conduct assessments on past clinical DDI studies with regard to study design, data interpretation and labeling recommendations. We expect these assessments will offer insights leading to more comprehensive recommendations on criteria for determination of the need for clinical DDI studies with ARAs; the optimal designs of clinical DDI studies with ARAs; better understanding and interpreting study results; and consistent oncology drug labeling on pH-dependent DDIs.