A Pharmacogenetics-Based Approach to Managing Gastroesophageal Reflux Disease: Current Perspectives and Future Steps

Figures & data

Table 1 CPIC Phenotype and Genotype Definitions with Associated Enzyme Activity

CYP2C19 Phenotype	Genotype	Diplotype Examples^b	Enzyme Activity
Ultrarapid Metabolizers (UMs)	Two increased function alleles	*17/*17	Markedly increased compared to NM
Rapid Metabolizers (RMs)	One normal function and one increased function allele	*1/*17	Increased compared to NM
Normal Metabolizers (NMs)	Two normal function alleles	*1/*1	Normal
Intermediate Metabolizers (IMs)	One normal function and one no function allele; or One no function and one increased function allele	*1/*2, *1/*3, *1/*8, *2/*17, *8/*17	Decreased compared to NM
Likely Intermediate Metabolizers (IMs)^a	One normal function and one decreased function allele; or One increased function and one decreased function allele; or Two decreased function alleles	*1/*9, *1/*10, *9/*10	Decreased compared to NM
Likely Poor metabolizers (PMs)^a	One no function and one decreased function allele	*2/*9, *2/*10	Markedly decreased
Poor metabolizers (PMs)	Two no function alleles	*2/*2, *3/*3, *8/*8	Markedly decreased/absent

Notes: ^aInsufficient evidence to definitively characterize decreased function alleles; ^bFull list available online, please refer to the CYP2C19 Diplotype-Phenotype table.^16,17

Figure 1 Frequencies of CYP2C19 phenotypes in biogeographical groups.

Table 2 Summary of Selected CYP2C19-PPI Pharmacokinetic Studies

Reference	Population/Study Design/PPI Intervention	CYP2C19 Phenotype /Genotype	Effect on PK/Other Outcome	Comments
Furuta et al (2001)^Citation22	18 healthy Japanese: NM = 7, IM = 7, PM = 4 Randomized double-blind crossover; single vs repeat (day 8) dosing of: Placebo vs LNZ 30 mg once daily; 5 NMs received LNZ 30 mg 4 times daily	NM^c IM^d PM	Significant difference between mean AUC relative ratios of NM:IM:PM = 1: 2.4: 5.4 Mean 24-hour pH significantly increased from once daily LNZ to 4 times daily dosing in NMs (p = 0.0024).	Frequent dosing of LNZ (ie, 30 mg 4 times daily) in NMs, achieved significant acid suppression and overcomes insufficiency previously seen with once daily dosing.
Hu et al (2007)^Citation23	18 healthy Chinese Han: NM = 6, IM = 6, PM = 6 Single (day 1) vs repeat (day 8) dosing of: OME 20 mg once daily	NM (*1/*1)^c IM (*1/*2, *1/*3)^d PM (*2/*2, *2/*3, *3/*3)	NM:IM:PM (AUC ratio; median intragastric pH ratio) Single dose of OME = NM (1.0; 2.2): IM (1.1; 3.7): PM (4.2; 5.4) Repeat OME dosing = NM (1.0; 4.4): IM (1.3; 4.7): PM (3.3; 6.0)	AUC values in PMs were 3–4 fold higher than NMs. Median intragastric pH significantly increased with repeated doses for NMs and IMs, but not PMs.
Hunfeld et al (2008)^Citation24	27 healthy Dutch: Study A (RM = 1, NM = 5, IM (*1/*2) = 4, IM (*2/ *17) = 1, PM = 0); Study B (RM = 6, NM = 6, IM (*1/*2) = 2 IM (*2/ *17) = 1, PM = 1) Randomized crossover studies; single vs repeat dosing of: Study A (LNZ 15 mg, OME 10 mg) or Study B (OME 20 mg, PNZ 40 mg) daily.	RM (*1⁄*17) NM (*1⁄*1) IM (*1⁄ *2, *2⁄*17) PM (*2⁄*2)	Study A (NM vs IM): Only IMs (*1/*2) showed significant acid-inhibition after one dose and repeat administration of LNZ and OME. Study B (NM vs RM): NMs and RMs showed no significant acid-inhibition after one dose OME. RMs and NMs showed significant acid-inhibition after repeat administration of OME and PNZ.	NMs and RMs may need higher PPI doses, especially during the first days of treatment or with on-demand therapy.
Lou et al (2009)^Citation25	9 healthy Taiwanese: NM = 3, IM = 3, PM = 3 Randomized crossover; 2 weeks washout period in between 3 study periods: ESO 40 mg once daily, 20 mg twice daily, or 10 mg 4 times daily for 7 days each.	NM (*1/*1)^c IM (*1/*2, *1/*3)^d PM (*2/*2, *3/*3, *2/*3)	Median % of time with pH < 4 (24-hour; Nocturnal) ESO 40 mg once daily: NM (32.5; 65.3), IM (32.2; 70.5), PM (26.7; 35.6) ESO 20 mg twice daily: NM (8.0; 10.8), IM (15.2, 23.0), PM (12.3; 12.6) ESO 10 mg 4 times daily: NM (7.7; 9.1), IM (13.7; 24.1), PM (20.8; 11.4)	ESO dosage divisions for same total daily dose of 40 mg (ie, 20 mg twice daily or 10 mg 4 times daily) significantly improved acid inhibition and nocturnal acid suppression in NMs, IMs, and PMs compared to ESO 40 mg once daily.
Hunfeld et al (2010)^Citation26	19 healthy Dutch: RM = 2, NM = 7, IM = 9, PM = 1 Randomized crossover; single (day 1) vs repeat (day 5) dosing of: ESO 40 mg or PNZ 20 mg once daily	RM (*1⁄*17) NM (*1⁄*1) IM (*1⁄ *2, *2⁄*17) PM (*2⁄*2)	Significantly higher % time with pH < 4 and median pH for IM compared to NM in PNZ (p = 0.025; 0.030), no significant difference in ESO (p = 0.165; 0.158). Mean AUC (mg⋅h/L): PNZ day 1: NM (3.8), IM (8.0); p = 0.02 PNZ day 5: NM (4.1), IM (8.9); p = 0.01 ESO day 1: NM (2.7), IM (4.2); p = 0.37 ESO day 5: NM (5.1), IM (8.2); p = 0.08	PK of PNZ is significantly influenced by CYP2C19 genotype, whereas ESO is not. Mean AUC was ~two-fold higher in IMs verses NMs following PNZ administration only.
Gawrońska-Szklarz et al (2012)^Citation27	32 healthy Polish: UM = 6, RM = 6, NM = 6, IM (*1/*2) = 6, IM (*2/*17) = 6, PM = 2 Single dose of PNZ 40 mg	UM (*17/*17) RM (*1/*17) NM (*1/*1) IM (*1/*2, *2/*17) PM (*2/*2)	Mean AUC (mg⋅h/L) UM (1.9), RM (2.1), NM (3.0), IM *1/*2 (4.4), IM *2/*17 (3.6), PM (15.2) Clearance (L/h) UM (24.4), RM (19.7), NM (15.2), IM *1/*2 (9.6), IM *2/*17 (11.6), PM (2.6)	Significantly lower PNZ levels and accelerated clearance in UMs vs NMs. 57% of interindividual variability in PNZ clearance was explained by CYP2C19 genotype.
Sahara et al (2013)^Citation28	40 healthy Japanese: NM = 15, IM = 15, PM = 10 Randomized crossover; twice-daily dosing of: OME 20 mg, ESO 20 mg, LNZ 30 mg, RPZ 10 mg	NM (*1/*1)^a IM (*1/*2, *1/*3) PM (*2/*2, *3/*3, *2/*3)	Median 24-hour intragastric pH OME = NM (5.0), IM (5.7), PM (6.6) LNZ = NM (4.7), IM (5.4), PM (6.4) ESO = NM (5.4), IM (5.6), PM (6.2) RPZ = NM (4.8), IM (5.0), PM (6.4)	CYP2C19 genotype-dependent differences in acid inhibition were smaller for ESO compared with OME, RPZ and LNZ.
Payan et al (2014)^Citation29	180 healthy Iranian: UM = 10, RM = 52, NM = 75, IM *1/*2 = 33, IM *2/*17 = 6, PM = 4 Single dose of OME 20 mg	UM (*17/*17) RM (*1/*17)^b NM (*1/*1)^b IM (*1/*2, *2/*17) PM (*2/*2)	Median hydroxylation index (HI) of OME: UM (0.4), RM (0.7), NM (0.8), IM *1/*2 (2.0), IM *2/*17 (1.7) No significant difference in median HI observed between RMs and NMs.	Like those with the *1/*2 diplotype, *2/*17 has intermediate metabolic capacity. Phenotype classification of IM consistent with CPIC.

Notes: Phenotypes above follow updated CPIC classification,¹⁵ phenotypes reported in the study that differ are as follows: ^aReferred to as rapid metabolizer (RM); ^bReferred to as extensive metabolizer (EM); ^cReferred to as homozygous extensive metabolizer (homEM); ^dReferred to as heterozygous extensive metabolizers (hetEM).

Abbreviations: PPI, proton pump inhibitors; OME, omeprazole; LNZ, lansoprazole; PNZ, pantoprazole; ESO, esomeprazole; RPZ, rabeprazole.

Table 3 Summary of Selected CYP2C19-PPI Outcome-Related Studies

Reference	Population/Study Design/PPI Intervention	CYP2C19 Phenotype /Genotype	Effect on PK/Other Outcome	Comments
Furuta et al (2002)^Citation30	65 Japanese patients with GERD (grades A-D): NM = 24, IM = 28, PM = 13 Single dose of LNZ 30 mg for 8 weeks	NM^d IM^e PM	Significant difference in GERD cure rates with LNZ in NM (46%) IM (68%) and PM (85%) phenotypes. The cure rate in NMs with a GERD grade of C or D was very low (17%). Significant difference in mean LNZ concentrations (ng/mL): NM (312.3), IM (439.9), PM (745.4).	In NMs with severe GERD (ie, grade C or D), treatment with a standard dose of LNZ is expected to result in therapeutic failure due to reduced LNZ plasma levels.
Furuta et al (2009)^Citation22	124 Japanese GERD patients treated with LNZ 30 mg once daily for 8 weeks prior to enrollment: NM = 54, IM = 56, PM = 14 If reflux occurred < once/week: LNZ maintenance dose reduced to 15 mg once daily If reflux occurred > once/week after dose decrease: LNZ dose restored to 30 mg once daily	NM (*1/*1)^a IM (*1/*2, *1/*3), PM (*2/*2, *3/*3, *2/*3)	% of patients who underwent a reduction of LNZ dose from 30 to 15 mg: NMs (33%), IMs (50%), and PMs (57%); however, among them, dose was restored to 30 mg for those with GERD recurrence: NMs (89%), IMs (79%), and PMs (50%). Hazard ratio (HR) of GERD recurrence: IM vs NM = 0.4 (CI: 0.2–0.9, p = 0.02) PM vs NM = 0.2 (CI: 0.1–0.7, p = 0.01)	NMs are at increased risk of GERD recurrence compared to IMs and PMs, especially when LNZ dose is decreased.
Chen et al (2010)^Citation31	200 Taiwanese patients with GERD (grades A and B): NM = 81, IM = 86, PM = 33 Randomized case-control study; PNZ 40 mg twice daily vs once daily + placebo at night for 8 weeks	NM^d IM^e PM	Sustained symptomatic response (SSR) for PNZ twice daily vs once daily Week 4: IMs (68% vs 42%, p = 0.03); NMs (55% vs 24%, p = 0.01); no significant difference for PM Week 8: IMs (95% vs 74%, p = 0.01); no significant difference for NMs and PMs	Twice daily dosing vs standard dosing of PNZ improves the symptomatic control for GERD patients with IM and NM phenotypes as early as 4 weeks.
Sheu et al (2012)^Citation32	240 Taiwanese patients with GERD (grades C-D). 200 of these patients included in 1-year on-demand therapy (ODT) and genotyped: NM = 51, IM = 108, PM = 41 Prospective study; continuous PNZ 40 mg/day for 6 months. If complete GERD remission, additional 12 months of ODT with PNZ 40 mg/day	NM^d IM^e PM	1-year cumulative success rate of ODT was significantly lower in NMs than IMs and PMs (51% vs 74% and 83%; p < 0.05). Mean monthly number of PNZ tablets was lower in PMs than NMs and IMs (11.5 vs 18.6 and 16.3, p < 0.05) for those with successful ODT during 1-year follow up.	PMs with severe GERD (Grade C or D) may benefit from ODT after achieving complete healing with continuous (6 months) PNZ dosing. This may reduce risk of long-term PPI side effects.
Ichikawa et al (2016)^Citation11	1355 GERD patients: NM = 604, IM = 526, PM = 225 Meta-analysis of 15 studies (Japan = 10, China = 2, Taiwan = 1, Iran = 1, Germany = 1) published up to 2014; different PPIs and doses.	NM (*1/*1)^a IM (*1/*2, *1/*3) PM (*2/*2, *3/*3, *2/*3)	Efficacy rates in NMs (52.2%); IMs (56.7%); PMs (61.3%) p = 0.047 NMs are at increased risk of being refractory to PPI compared to PMs (odds ratio (OR) 1.7, CI: 1.0–2.7, p = 0.04)	NMs are at an increased risk of PPI refractoriness for GERD treatment. Cure rates were similar among all phenotypes for ESO and RPZ, but not for LNZ and PNZ.
Franciosi et al (2018)^Citation14	74 children with GERD; Cases: UM = 5, RM = 16; Controls: NM = 37, IM = 16 Retrospective cohort study; different PPIs and doses	UM (*17/*17) RM (*1/*17) NM (*1/*1) IM (*1/*2, *1/*8, *2/*17)	Strong association of poor pH probe testing outcomes (ie, insufficient acid suppression) in RM and UMs compared to NMs and IMs. RMs and UMs displayed a 2-fold higher time with pH < 4 compared to NMs and IMs (76.5 vs 33.5 minutes, p = 0.03).	PPI therapy in children with RM and UM phenotypes may be better optimized with CYP2C19 genotype-guided dosing prior to pH probe testing.
Franciosi et al (2018)^Citation33	Cases: 34 children who underwent anti-reflux surgery (ARS) after failing PPI therapy; UM = 3, RM = 11, NM = 16, IM = 4, PM = 0 Controls: 457 children with no history of ARS; UM = 21, RM = 117, NM = 201, IM = 102, PM = 16 Retrospective case-control; different PPIs and doses	UM (*17/*17)^b RM (*1/*17)^b NM (*1/*1) IM (*1/*2, *1/*8)^f (*2/*17, *8/*17)^c PM (*2/*2, *2/*8)	Frequency of patients ARS vs no-ARS (below frequencies differs from study; adjusted for phenotype categories to the left): ARS: UM (8.8%), RM (32.4%), NM (47.1%), IM (11.7%), PM (0%) No-ARS: UM (4.6%), RM (25.6%), NM (44%), IM (22.3%), PM (3.5%) NM (OR 8.6, CI 1.1–63.3, p = 0.04), RM and UM (OR 9.8, CI 1.3–76.6, p = 0.03) phenotypes were significant predictors of ARS relative to no-ARS.	IM and PM are under-represented in ARS, suggesting ARS may be avoided with more aggressive PPI dosing for NMs, RMs, and UMs. Preemptive CYP2C19 testing may be beneficial for this population.

Notes: Phenotypes above follow updated CPIC classification,¹⁵ phenotypes reported in the study that differ are as follows: ^aReferred to as rapid metabolizer (RM); ^bReferred to as extensive metabolizer (EM); ^cReferred to normal metabolizer (NM); ^dReferred to as homozygous extensive metabolizer (homEM); ^eReferred to as heterozygous extensive metabolizers (hetEM), ^fReferred to as poor metabolizer (PM).

Abbreviations: PPI, proton pump inhibitors; OME, omeprazole; LNZ, lansoprazole; PNZ, pantoprazole; ESO, esomeprazole; RPZ, rabeprazole.

Figure 2 Recommendations for PGx testing and PGx-guided PPI dosing for patients with GERD symptoms despite PPI treatment (Algorithm based on CPIC guidelines in conjunction with ACG guidelines).

Note: *If PGx testing is performed, at minimum, ensure Tier 1 CYP2C19 alleles (ie, *2, *3, *17) are included in genotyping assays.

Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C19 and proton pump inhibitor dosing. Clin Pharmacol Ther. 2021;109(6):1417–1423. doi:10.1002/cpt.2015

 PubMed Web of Science ®Google Scholar

PharmGKB. Gene-specific information tables for CYP2C19. Available from: https://www.pharmgkb.org/page/cyp2c19RefMaterials. Accessed May 18, 2023.

 Google Scholar

Furuta T, Sugimoto M, Kodaira C, et al. CYP2C19 genotype is associated with symptomatic recurrence of GERD during maintenance therapy with low-dose lansoprazole. Eur J Clin Pharmacol. 2009;65(7):693–698. doi:10.1007/s00228-009-0628-5

 PubMed Web of Science ®Google Scholar

Hu XP, Xu JM, Hu YM, Mei Q, Xu XH. Effects of CYP2C19 genetic polymorphism on the pharmacokinetics and pharmacodynamics of omeprazole in Chinese people. J Clin Pharm Ther. 2007;32(5):517–524. doi:10.1111/j.1365-2710.2007.00851.x

 PubMed Web of Science ®Google Scholar

Hunfeld NG, Mathot RA, Touw DJ, et al. Effect of CYP2C19*2 and *17 mutations on pharmacodynamics and kinetics of proton pump inhibitors in Caucasians. Br J Clin Pharmacol. 2008;65(5):752–760. doi:10.1111/j.1365-2125.2007.03094.x

 PubMed Web of Science ®Google Scholar

Lou HY, Chang CC, Sheu MT, Chen YC, Ho HO. Optimal dose regimens of esomeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism. Eur J Clin Pharmacol. 2009;65(1):55–64. doi:10.1007/s00228-008-0552-0

 PubMed Web of Science ®Google Scholar

Hunfeld NG, Touw DJ, Mathot RA, et al. A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism. Aliment Pharmacol Ther. 2010;31(1):150–159. doi:10.1111/j.1365-2036.2009.04150.x

 PubMed Web of Science ®Google Scholar

Gawrońska-Szklarz B, Adamiak-Giera U, Wyska E, et al. CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers. Eur J Clin Pharmacol. 2012;68(9):1267–1274. doi:10.1007/s00228-012-1252-3

 PubMed Web of Science ®Google Scholar

Sahara S, Sugimoto M, Uotani T, et al. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole. Aliment Pharmacol Ther. 2013;38(9):1129–1137. doi:10.1111/apt.12492

 PubMed Web of Science ®Google Scholar

Payan M, Rouini MR, Tajik N, Ghahremani MH, Tahvilian R. Hydroxylation index of omeprazole in relation to CYP2C19 polymorphism and sex in a healthy Iranian population. Daru. 2014;22(1):81. doi:10.1186/s40199-014-0081-6

 PubMedGoogle Scholar

Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med. 2017;19(2):215–223. doi:10.1038/gim.2016.87

 PubMed Web of Science ®Google Scholar

Furuta T, Shirai N, Watanabe F, et al. Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole. Clin Pharmacol Ther. 2002;72(4):453–460. doi:10.1067/mcp.2002.127637

 PubMed Web of Science ®Google Scholar

Chen WY, Chang WL, Tsai YC, Cheng HC, Lu CC, Sheu BS. Double-dosed pantoprazole accelerates the sustained symptomatic response in overweight and obese patients with reflux esophagitis in Los Angeles grades A and B. Am J Gastroenterol. 2010;105(5):1046–1052. doi:10.1038/ajg.2009.632

 PubMed Web of Science ®Google Scholar

Sheu BS, Cheng HC, Yeh YC, Chang WL. CYP2C19 genotypes determine the efficacy of on-demand therapy of pantoprazole for reflux esophagitis as Los-Angeles grades C and D. J Gastroenterol Hepatol. 2012;27(1):104–109. doi:10.1111/j.1440-1746.2011.06848.x

 PubMed Web of Science ®Google Scholar

Ichikawa H, Sugimoto M, Sugimoto K, Andoh A, Furuta T. Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis. J Gastroenterol Hepatol. 2016;31(4):716–726. doi:10.1111/jgh.13233

 PubMed Web of Science ®Google Scholar

Franciosi JP, Mougey EB, Williams A, et al. Association between CYP2C19*17 alleles and pH probe testing outcomes in children with symptomatic gastroesophageal reflux. J Clin Pharmacol. 2018;58(1):89–96. doi:10.1002/jcph.977

 PubMed Web of Science ®Google Scholar

Franciosi JP, Mougey EB, Williams A, et al. Association between CYP2C19 extensive metabolizer phenotype and childhood anti-reflux surgery following failed proton pump inhibitor medication treatment. Eur J Pediatr. 2018;177(1):69–77. doi:10.1007/s00431-017-3051-4

 PubMed Web of Science ®Google Scholar