CYP2C19 polymorphism affects single-dose pharmacokinetics of oral pantoprazole in healthy volunteers

Abstract

ObjectivesPantoprazole is metabolized by cytochrome P450 2 C19, which shows genetic polymorphism. The effect of CYP2C19 polymorphism on single-dose pharmacokinetics of oral pantoprazole in healthy volunteers was evaluated.MethodsPantoprazole pharmacokinetics was determined in 32 healthy volunteers after a 40-mg single oral dose of the drug.ResultsCarriers of CYP2C19*2/*2 (n = 2) were characterized by higher, starting from 3.5 h post dose, plasma concentrations of pantoprazole in comparison to wild-type (CYP2C19*1/*1, n = 6) volunteers. In subjects with CYP2C19*17/*17 genotype (n = 6) significantly lower plasma concentrations of the drug vs CYP2C19*1/*1 carriers, were observed from 3.0 h after oral pantoprazole administration. Carriers of CYP2C19*1/*17 (n = 6) and CYP2C19*2/*17 (n = 6) displayed concentration–time profiles comparable to wild-type subjects. CYP2C19*2/*2 volunteers showed a decrease in terminal elimination rate constant (λz) by 83.3%, prolongation of terminal half-life (t½) by 572%, a rise in area under the concentration–time curve (AUC) and mean residence time (MRT) by 506% and 259% respectively. Heterozygotes, i.e.. CYP2C19*1/*2 vs CYP2C19*1/*1 were characterized by higher AUC (4.38 ± 1.00 mg⋅h/L vs 3.00 ± 1.02 mg⋅h/L, p < 0.05) and Cmax (2.13 ± 0.42 mg/L vs 1.61 ± 0.35 mg/L, p < 0.05) respectively. A significant reduction in MRT (3.83 ± 0.82 h vs 2.73 ± 0.23 h, p < 0.05) in carriers of CYP2C19*17/*17 vs CYP2C19*1/*1 genotypes was observed. Population modeling confirmed the influence of *1/*2, *2/*2, and *17/*17 genotypes on the pharmacokinetics of pantoprazole. The lowest population oral clearance was assessed in the carriers of genotype *2/*2 (3.68 L/h) and the highest value in subjects with genotype *17/*17 (31.13 L/h).ConclusionThese data suggest that CYP2C19 polymorphism is an important determinant of pantoprazole pharmacokinetics.

Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine

“…NM may be at risk of lower plasma concentrations of LNZ with once-daily administration of 30 mgFuruta et al [42] 15 healthy Japanese: NM = 5,IM = 4,PM = 6; OME 20 mgAUC ratio of NM:IM:PM = 1:3.3: 12.2Intragastric pH in NM:IM:PM = 2.1: 3.3:4.5 CYP2C19 significantly affects PK and PD of OMEQiao et al [45] 18 healthy Chinese: NM = 6,IM = 6,PM = 6; randomized crossover; OME 20 mg, LNZ 30 mg or RPZ 20 mgAUC ratio of NM:IM:PMOME = 1:2.8:7.5LNZ = 1:1.7:4.0RPZ = 1:1.6:3.7 CYP2C19 significantly influences PK of the three PPIs, however with a lesser extent in RPZLeiri et al [47] 15 healthy Japanese: NM = 5,IM = 5,PM = 5; randomized crossover to once-daily dose; LNZ 30 mg or RPZ 10 mgAUC ratio of NM:IM: PMLNZ = 1:1.7:3.9RPZ = 1:1.7:3.8 CYP2C19 influenced PK of both LNZ and RPZHu YM et al [46] 20 healthy Chinese: NM = 7, IM = 6,PM = 7; single daily dose of RPZ 20 mgAUC ratio of NM:IM:PM = 1.0:1.1: 1.7No difference in median intragastric pH or percent of time pH > 4 between three phenotypes CYP2C19 influenced PK of RPZ with no significant effect on PDAdachi et al [48] 20 healthy Japanese: NM = 7,IM = 9, PM = 4; randomized crossover to RPZ 20 mg or LNZ 30 mgNighttime pH in NM:IM:PMLNZ = 1.8: 2.2: 5.9RPZ = 3.1: 4.3: 4.0Acid inhibition is significantly influenced by CYP2C19 genotype in LNZ but not RPZSahara et al [51] 40 healthy Japanese: NM = 15,IM = 15, PM = 10; randomized crossover to twice-daily; OME 20 mg, ESO 20 mg, LNZ 30 mg, RPZ 10 mgMedian pH in NM:IM:PMOME = 5.0: 5.7: 6.6LNZ = 4.7: 5.4: 6.4ESO = 5.4: 5.6: 6.2RPZ = 4.8: 5.0: 6.4Acid inhibition is significantly influenced by CYP2C19 with lesser magnitude in ESO and RPZSugimoto et al [49] 183 healthy Japanese; prospective cohort; once-daily doses; OME 20 mg, LNZ 30 mg, RPZ 10 mg;OME: NM = 16, IM = 19, PM = 15LNZ: NM = 35, IM = 21, PM = 12RPZ: NM = 23, IM = 23,PM = 19Median pH in NM:IM:PMOME = 3.8: 4.8: 5.2LNZ = 4.5: 4.8: 5.2RPZ = 4.8: 5.0:5.9Median pH is significantly influenced by CYP2C19 . In NM phenotype, pH was significantly highest in RPZ compared to other PPIsGawronska-Szklarz et al [7] **32 healthy Polish: NM = 6, RM = 6,UM = 6,IM(*1/*2) = 6,IM(*2/*17) = 6,PM = 2; single dose; PNZ 40 mgAUC ratio in NM:IM:PM = 1: 1.5: 5.0AUC ratio in NM:RM:UM = 1: 0.7: 0.6…”

“…That the *17 haplotype is associated with enhanced CYP2C19 activity and reduced PPI exposure is supported by several studies. For example, individuals with *17 allele had lower plasma concentrations of pantoprazole compared to NM [7,57,58]. Hunfeld et al investigated the effect of CYP2C19 variants: *2–*6 and *17 on PK parameters of different doses of PPIs (omeprazole 10 mg and 20 mg, lansoprazole 15 mg and pantoprazole 40 mg, Table 3) and percentage of time with intragastric pH > 4 post PPI administration [58].…”

“…Although many nongenetic factors can influence PPIs, variability due to CYP2C19 genotype is significant and accounts for large percent of the PK variability of PPIs. Gawronska-Szklarz et al, for example, demonstrated that 57% of variability in pantoprazole population clearance in adults was attributed to CYP2C19 genotype [7]. …”

Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype

“…An additional limitation is that we did not perform area under the plasma concentration-time curve (AUC) or pharmacodynamic gastric pH testing on the current cohort. However, past researchers have shown that patients with one loss-offunction allele for CYP2C19 consistently display higher peak proton pump inhibitor drug levels (13), higher AUCs (10,11,15,16,19), and reduced gastric pH (16,19), which supports the likelihood that future patients with one loss-of-function allele given a PPI will experience greater drug exposure compared with patients with two normal alleles.…”

“…Several loss-offunction CYP2C19 single-nucleotide polymorphisms are fairly common in the population and consistently associate with higher PPI levels (13)(14)(15)(16). From the SARCA cohort, we previously reported loss-offunction allele frequencies of 13, 20, and 30% for white, African American, and Asian children, respectively (10,13).…”