New Proton Pump Inhibitor Dosing Recommendations Address Pediatric Patients
Using CYP2C19 Genotype Variations to Guide Therapy
Proton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of a variety of conditions, including gastroesophageal reflux disease (GERD), gastric and duodenal ulcers, erosive esophagitis, eosinophilic esophagitis, Helicobacter pylori infection and pathological hypersecretory conditions in adults and children.
Most PPIs are extensively metabolized into inactive metabolites primarily by the hepatic cytochrome P450 2C19 (CYP2C19) enzyme. CYP2C19 genotypes have been linked to variability in PPI exposure and treatment response, with lower exposure associated with treatment failure and higher exposure associated with improved treatment efficacy.1
Representing the Needs of Pediatric Patients
Recently, Valentina Shakhnovich, MD, Physician-Scientist with the Division of Pediatric Gastroenterology, Hepatology and Nutrition and Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation at Children’s Mercy Kansas City, served as a co-author on the international guidelines for dosing PPIs published in August 2020 by the Clinical Pharmacogenetics Implementation Consortium (CPIC). The organization’s goal is to bring precision therapeutics to the patient’s bedside.
Dr. Shakhnovich, who has conducted novel research aimed at understanding the sources of variability in PPI treatment response in children, was the only pediatric gastroenterologist invited to contribute to the guidelines, which were developed based on expert opinion from pharmacogenetics leaders in the field.
Therapy Targeted to the CYP2C19 Gene
PPIs have been among the most commonly prescribed medications in adults and children, due in part to the perception that they have a high safety-to-risk profile. However, a large body of evidence is emerging that links adverse events with long-term PPI use.2 Adverse events have included electrolyte imbalances (e.g., hypomagnesemia), infections, kidney disease and bone fractures.
Clinical CYP2C19 genotype testing results can provide clinicians with information to facilitate appropriate dose selection of PPIs. Essentially, the guidelines created dosing recommendations for first-generation PPIs, including omneprazole, lansoprazole, pantoprazole and dexlansoprazole. Based on genetic testing, patients can be divided into seven phenotype categories, ranging from ultra-rapid metabolizers to poor metabolizers. The guidelines recommend increasing the standard starting daily dose for ultra-rapid metabolizers, as well as for normal and rapid metabolizers when treating specific disorders like erosive esophagitis and H. pylori gastritis, while reducing the standard starting dose for those who are intermediate and poor metabolizers, especially if considering long-term PPI therapy.
Pediatric Recommendations
The CYP2C19-guided PPI dosing recommendations also apply to pediatric patients. PPI use in children is common and continues to increase. PPIs have U.S. Food and Drug Administration-approved indications in children for the short-term treatment of symptomatic GERD, healing of erosive esophagitis, treatment of peptic ulcer disease, and eradication of H. pylori. They are also considered the standard of care for pediatric eosinophilic esophagitis. However, off-label and potentially inappropriate use of long-term PPI therapy in children is also common, particularly in infants less than 1 year of age for uncomplicated, physiologic, gastroesophageal reflux and colic.
For children older than 1 year, there is emerging evidence that CYP2C19 genetic variation influences PPI pharmacokinetics and treatment response. A recent pilot study of CYP2C19 genotype-guided dosing of PPIs in children has been promising, and additional studies are ongoing. These investigations support genotype-based optimization of PPI therapy for children. However, very low clearance in preterm infants and infants less than 2-3 months old makes recommendations in the neonatal population more challenging to support.
Utilizing Noninvasive Breath Test Technology to Identify CYP2C19 Phenotype
Dr. Shakhnovich is conducting clinical research investigating the use of noninvasive breath test technology to identify children who would benefit from PPI dose adjustment based on the new CPIC treatment guidelines. The team involved in this line of research is assessing the utility of the 13C-pantoprazole breath test, which only requires the patient to breathe into a bag in lieu of a blood draw for genetic testing, with promising results.
Dr. Shakhnovich and her collaborators at the University of Missouri-Kansas City, University of Kansas Medical Center, The Center for Children’s Healthy Lifestyles and Nutrition, and Texas Christian University will present their findings in March 2021 at the American Society for Clinical Pharmacology and Therapeutics virtual meeting. A sneak peek at the data suggests that this test could offer a clinically useful, noninvasive method to identify children who would benefit from PPI dose escalation or dose reduction in as little as 60 minutes, without the need for a blood draw.
Long-term Benefits of PPI Guidance in the Pediatric Population
The benefit of using CYP2C19 genotype information to guide PPI therapy is that patients with phenotypes predictive of lower plasma drug concentrations from a given PPI dose can be identified upfront, and prescribed an increased starting dose of medication to increase the likelihood of PPI efficacy.
Conversely, for patients on chronic PPI therapy with phenotypes predictive of slower drug clearance and therefore higher systemic exposure to PPIs over time, clinicians may want to consider a dose reduction to minimize the risk of toxicity associated with long-term PPI use (overexposure).
These recommendations provide essential guidance, especially for pediatric patients who may begin PPI treatment at an early age and who may potentially be exposed to these medications over a much longer period of time than adults.
Learn more about Pediatric Gastroenterology at Children’s Mercy
Valentina Shakhnovich, MD, Pediatric Gastroenterologist and Clinical Pharmacologist; Associate Professor of Pediatrics, University of Missouri-Kansas City School of Medicine
vshakhnovich@cmh.edu
(816) 302-3068
For consults, admissions or transport call: 1 (800) GO MERCY / 1 (800) 466-3729.
Children’s Mercy Kansas City is an independent, non-profit, 390-bed pediatric health system, providing over half a million patient encounters each year for children from across the country. Children’s Mercy is ranked by U.S. News & World Report in all ten specialties. We have received Magnet® recognition five times for excellence in nursing services. In affiliation with the University of Missouri-Kansas City, our faculty of nearly 800 pediatric specialists and researchers is actively involved in clinical care, pediatric research and educating the next generation of pediatricians and pediatric subspecialists. The Children’s Mercy Research Institute (CMRI) integrates research and clinical care with nationally recognized expertise in genomic medicine, precision therapeutics, population health, health care innovation and emerging infections. In 2021 the CMRI moved into a nine-story, 375,000-square-foot space emphasizing a translational approach to research in which clinicians and researchers work together to accelerate the pace of discovery that enhances care.
References
Lima JJ, Thomas CD, Barbarino J, Desta Z, Van Driest SL, El Rouby N, Johnson JA, Cavallari LH, Shakhnovich V, Thacker DL, Scott SA, Schwab M, Uppugunduri CR, Formea CM, Franciosi JP, Sangkuhl K, Gaedigk A, Klein TE, Gammal RS, Furuta T. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. https://cpicpgx.org/guidelines/cpic-guideline-for-proton-pump-inhibitors-and-cyp2c19/.
Jaynes M, Kumar AB. The Risks of Long-term Use of Proton Pump Inhibitors: A Critical Review. Ther. Adv. Drug. Saf. 10, 2042098618809927 (2018) https://doi.org/10.1177/2042098618809927.