. 2023 Jun 23;16:645–664. doi: 10.2147/PGPM.S371994

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)³⁰	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)²²	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)³¹	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)³²	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)¹¹	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)¹⁴	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)³³	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.