Effects of obesity on the pharmacology of proton pump inhibitors: current understanding and future implications for patient care and research

ABSTRACT

Introduction

In the United States, obesity affects approximately ⅖ adults and ⅕ children, leading to increased risk for comorbidities, like gastroesophageal reflux disease (GERD), treated increasingly with proton pump inhibitors (PPIs). Currently, there are no clinical guidelines to inform PPI dose selection for obesity, with sparse data regarding whether dose augmentation is necessary.

Areas Covered

We provide a review of available literature regarding the pharmacokinetics (PK), pharmacodynamics (PD), and/or metabolism of PPIs in children and adults with obesity, as a step toward informing PPI dose selection.

Expert Opinion

Published PK data in adults and children are limited to first-generation PPIs and point toward reduced apparent oral drug clearance in obesity, with equipoise regarding obesity impact on drug absorption. Available PD data are sparse, conflicting, and limited to adults. No studies are available to inform the PPI PK→PD relationship in obesity and if/how it differs compared to individuals without obesity. In the absence of data, best practice may be to dose PPIs based on CYP2C19 genotype and lean body weight, so as to avoid systemic overexposure and potential toxicities, while monitoring closely for efficacy.

KEYWORDS:

• CYP2C19
• GERD
• obesity
• pediatric obesity
• proton pump inhibitors
• weight-based dosing

Article highlights

• No clinical guidelines are available to guide PPI dosing for individuals with obesity, and very few studies have explored appropriate approaches to drug-dose selection for this growing patient population disproportionately affected by acid-related comorbidities

• Evidence to date suggests that patients with obesity experience reduced CYP2C19-mediated drug clearance for the 1st generation of PPIs (e.g. omeprazole, pantoprazole), with no consensus regarding the impact of obesity of PPI absorption

• Data linking observations of altered PPI pharmacokinetics in obesity with pharmacodynamic end points are lacking, with no consensus regarding the impact of obesity on the PPI dose → response relationship based on the sparse pharmacodynamic data available

• While additional pharmacology knowledge is generated through inclusion of individuals with obesity into clinical trials, LBW-based dosing that takes into account CYP2C19 genotype may be the most prudent dosing strategy for patients with obesity

This box summarizes key points contained in the article.

Declaration of interest

V Shakhnovich receives/received financial and salary support to investigate the effect of obesity on proton pump inhibitors in children from the National Institutes of Health (5K23 DK115827-03) and from the National Center for Advancing Translational Sciences (L40 TR000598). D Gonzalez Receives research support from Nabriva Therapeutics through a contract with the University of North Carolina at Chapel Hill; and serves as a Consultant for Tellus Therapeutics, focusing on neonatal drug development. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health (5K23 DK115827-03 L40 TR000598), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R01HD096435-05, 5R01HD102949-02, HHSN275201000003I), Pediatric Trials Network (NICHD-2012-PAN01), and the George Ferry Young Investigator Development Award.