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4. Novel Implementation of Genotype‐Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial

Author

Cicali, Emily J., primary, Blake, Kathryn, additional, Gong, Yan, additional, Mougey, Edward B., additional, Al‐Atrash, Hadeel, additional, Chambers, Nancy, additional, Denham, Jolanda, additional, Evans, Jonathan, additional, George, Donald E., additional, Gomez, Roberto, additional, Palomo, Pablo, additional, Taufiq, Salik, additional, Johnson, Julie A., additional, Lima, John J., additional, and Franciosi, James P., additional

Published
2018
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6. Novel Implementation of Genotype‐Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial.

Author

Cicali, Emily J., Blake, Kathryn, Gong, Yan, Mougey, Edward B., Al‐Atrash, Hadeel, Chambers, Nancy, Denham, Jolanda, Evans, Jonathan, George, Donald E., Gomez, Roberto, Palomo, Pablo, Taufiq, Salik, Johnson, Julie A., Lima, John J., and Franciosi, James P.

Subjects
OMEPRAZOLE, PROTON pump inhibitors, DRUG prescribing, GASTROESOPHAGEAL reflux in children, SENSITIVITY analysis
Abstract

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype‐guided pediatric dosing of PPI medications. Children aged 5–17 years old with gastric‐acid‐related conditions were randomized to receive either conventional dosing of a PPI or genotype‐guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype‐guided dosing arm (P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype‐guided dosing arm. The number of participants who reported an infection was marginally lower in genotype‐guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype‐guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype‐guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI‐associated infections. A future large scale randomized clinical trial of CYP2C19 genotype‐guided pediatric dosing of PPI medications in children is warranted. [ABSTRACT FROM AUTHOR]

Published
2019
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7. CYP2C19and STAT6Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis

Author

Mougey, Edward B., Williams, Andre, Coyne, Ashlan J. Kunz, Gutiérrez-Junquera, Carolina, Fernández-Fernández, Sonia, Cilleruelo, Maria Luz, Rayo, Ana, Echeverría, Luis, Román, Enriqueta, González Lois, Carmen, Chao, Montserrat, Al-Atrash, Hadeel, Lima, John J., and Franciosi, James P.

Abstract

Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19and STAT6associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19and STAT6influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C19*17(P= 0.35). In children who received a PPI dose between =1.54 and ?2.05 mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C19*17associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P= 0.031). Carriage of STAT6allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P= 0.028), whereas carriage of STAT6rs324011 synergizes with CYP2C19*17to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P= 0.022; CYP2C19*17OR [95% CI] = 8.19[1.42, 50.57], P= 0.023). Common variants in CYP2C19and STAT6associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.

Published
2019
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9. Novel Implementation of Genotype-Guided Proton Pump Inhibitor Medication Therapy in Children: A Pilot, Randomized, Multisite Pragmatic Trial.

Author

Cicali EJ, Blake K, Gong Y, Mougey EB, Al-Atrash H, Chambers N, Denham J, Evans J, George DE, Gomez R, Palomo P, Taufiq S, Johnson JA, Lima JJ, and Franciosi JP

Subjects
Adolescent, Child, Child, Preschool, Cytochrome P-450 CYP2C19 metabolism, Dose-Response Relationship, Drug, Drug Dosage Calculations, Feasibility Studies, Female, Follow-Up Studies, Gastroesophageal Reflux genetics, Genotyping Techniques, Humans, Male, Pilot Projects, Proton Pump Inhibitors pharmacokinetics, Cytochrome P-450 CYP2C19 genetics, Gastroesophageal Reflux drug therapy, Precision Medicine methods, Proton Pump Inhibitors administration & dosage
Abstract

The efficacy of proton pump inhibitor (PPI) medications is highly dependent on plasma concentrations, which varies considerably due to cytochrome P450 (CYP2C19) genetic variation. We conducted a pragmatic, pilot study of CYP2C19 genotype-guided pediatric dosing of PPI medications. Children aged 5-17 years old with gastric-acid-related conditions were randomized to receive either conventional dosing of a PPI or genotype-guided dosing for a total of 12 weeks. Sixty children (30 in each arm) were enrolled and had comparable baseline characteristics. The mean daily omeprazole equivalent dose prescribed to participants across metabolizer phenotype groups was significantly different in the genotype-guided dosing arm (P < 0.001), but not in the conventional dosing arm. Prescribers waited for the genotype result before prescribing the PPI medication for 90% of the participants in the genotype-guided dosing arm. The number of participants who reported an infection was marginally lower in genotype-guided dosing vs. conventional dosing (20% vs. 44%; P = 0.07). Sinonasal symptoms were higher in the conventional dosing arm as compared with genotype-guided dosing arm: (2.6 (2.0, 3.4) vs. 1.8 (1.0, 2.3), P = 0.031). CYP2C19 genotype-guided PPI therapy is feasible in a clinical pediatric setting, well accepted by providers, resulted in differential PPI dosing, and may reduce PPI-associated infections. A future large scale randomized clinical trial of CYP2C19 genotype-guided pediatric dosing of PPI medications in children is warranted., (© 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Published
2019
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