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

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.

Prescribing Prevalence of Medications With Potential Genotype-Guided Dosing in Pediatric Patients

“…[22][23][24][25][26] CPIC guidelines are available for the CYP2D6 substrates ondansetron, 27 select opioids, 28,29 tricyclic antidepressants, 30,31 atomoxetine, 12 tamoxifen, 32 and selective serotonin reuptake inhibitors 33 ; there are also CPIC guidelines for the CYP2C19 substrates tricyclic antidepressants, 30,31 selective serotonin reuptake inhibitors, 33 clopidogrel, 34,35 and voriconazole. 11 Initial data support the utility of CYP2D6 or CYP2C19 genotypeguided therapies for pediatrics [24][25][26] If this test examines a panel of genes and these results are included in the EHR with associated clinical decision support, they could be used preemptively at the point of prescribing all future medications related to those genes (eg, granisetron could be used instead of ondansetron for acute nausea in a patient with a CYP2D6 ultrarapid metabolizer phenotype). This illustrates the potential longitudinal utility of pharmacogenetic test results from childhood even into adulthood, which can be further facilitated by enhanced EHR interoperability, enabling dissemination of laboratory results across health care systems.…”

Design and Early Implementation Successes and Challenges of a Pharmacogenetics Consult Clinic

“…Due to the established infrastructure of the Precision Medicine Program, in-house testing for CYPC19 and CYP2D6 was already available to guide prescribing of commonly used medications in the primary care setting, such as SSRIs [ 29 ], certain opioids (i.e., codeine, tramadol, hydrocodone, and oxycodone) [ 28 , 30 ], and proton pump inhibitors (PPIs) [ 31 , 32 ]. Health system records were queried for the year prior to clinic launch (1 September 2015–31 August 2016) for the number of patients at UF Health primary care clinics prescribed these medications.…”

Pediatric pharmacogenomics: challenges and opportunities: on behalf of the Sanford Children’s Genomic Medicine Consortium

“…The University of Florida implemented a custom array with 256 clinically actionable genetic polymorphisms [18]. Pediatric focused gene implementations by the University of Florida include TPMT/thiopurines [19] and CYP2C19/ proton pump inhibitors (in partnership with Nemours Children's Specialty Care, Jacksonville, FL and Nemours Children's Hospital, Orlando, FL [20]. Boston Children's Hospital has focused on children with significant adverse drug reactions or failed treatment using either single gene sequencing tests for TPMT and CYP2C9/VKORC1 or microarray panels testing up to 225 SNPs [13].…”