Proton pump inhibitors in pediatrics : mechanism of action, pharmacokinetics, pharmacogenetics, and pharmacodynamics

Abstract

Proton pump inhibitors (PPIs) have become some of the most frequently prescribed medications for treatment of adults and children. Their effectiveness for treatment of peptic conditions in the pediatric population, including gastric ulcers, gastroesophageal reflux disease (GERD), and Helicobacter pylori infections has been established for children older than 1 year. Studies of the preverbal population of neonates and infants have identified doses that inhibit acid production, but the effectiveness of PPIs in the treatment of GERD has not been established except for the recent approval of esomeprazole treatment of erosive esophagitis in infants. Reasons that have been proposed for this are complex, ranging from GERD not occurring in this population to a lack of histologic identification of esophagitis related to GERD to questions about the validity of symptom scoring systems to identify esophagitis when it occurs in infants. The effectiveness of PPIs relates to their structures, which must undergo acidic activation within the parietal cell to allow the PPI to be ionized and form covalent disulfide bonds with cysteines of the H(+)-K(+)-adenosine triphosphatase (H(+)-K(+)-ATPase). Once the PPI binds to the proton pump, the pump is inactivated. Some PPIs, such as omeprazole and rabeprazole bind to cysteines that are exposed, and their binding can be reversed. After irreversible chemical inhibition of the proton pump, such as occurs with pantoprazole, the recovery of the protein of the pump has a half-life of around 50 h. Cytochrome P450 (CYP) 2C19 and to a lesser degree CYP3A4 clear the PPIs metabolically. These enzymes are immature at birth and reach adult levels of activity by 5-6 months after birth. This parallels studies of the maturation of CYP2C19 to adult levels by roughly the same age after birth. Specific single nucleotide polymorphisms of CYP2C19 reduce clearance proportionally and increase exposure and prolong proton pump inhibition. Prolonged treatment of pediatric patients with PPIs has not caused cancer or significant abnormalities.

Figures

Fig. 1

General chemical structure and mechanism of action of proton pump inhibitors (PPIs). Reproduced from Litalien et al. [3], with permission from Springer International Publishing AG (© Adis Data Information BV [2005]. All rights reserved.) ATPase adenosine triphosphatase, CYP cytochrome P450, P-gp P-glycoprotein, pKa negative logarithm of the acid ionization constant

Fig. 2

The metabolic pathways of the proton pump inhibitors and the major cytochrome P450 (CYP) isoenzymes involved. The thicker the arrow, the larger the contribution of the CYP isoforms to the metabolic pathway. Reproduced from Litalien et al. [3], with permission from Springer International Publishing AG (© Adis Data Information BV [2005]. All rights reserved.)

Fig. 3

Association between age and the weight-normalized apparent oral clearance (CL/F) of pantoprazole in neonates, infants, children, and adolescents. Dashed lines represent apparent ‘best fit’ from non-linear (for subjects from birth through 0.5 years of age) and linear (for subjects from 0.5 to 16 years of age) regressions of the data and are provided to illustrate association between CL/F and age. Data were obtained from a series of labeling studies conducted by the study sponsor and subjected to a population-based pharmacokinetic analysis to explore age-associated effects on disposition [35]

Fig. 4

a Association between cytochrome P450 (CYP) 2C19 protein expression in the human fetus and neonate, shown by dark circles. Open and grey circles represent outliers based on analysis of residuals that were not used in the regression analysis [36]. Reproduced from Koukouritaki et al. [36], © The American Society for Pharmacology and Experimental Therapeutics 2004, with permission. EGA estimated gestational age, PNA postnatal age. b The association between postnatal age and the apparent oral clearance (CL/F) of pantoprazole following a single oral dose of either 1.25 mg (dark circles) or 2.5 mg (grey circles). Triangles denote patients with a CYP2C19 genotype that would be predictive of a poor-metabolizer phenotype. A regression line (p < 0.05 for r2) is shown to illustrate the association between CL/F and age. Reproduced from Ward et al. [22], © Springer-Verlag 2010, with the kind permission of Springer Science + Business Media

Fig. 5

Relationship between cytochrome P450 2C19 genotype and the apparent terminal elimination rate constant (Kel) for pantoprazole in children and adolescents. Boxes reflect interquartile range, lines in the boxes depict the mean values, and whiskers indicate the 10th and 90th percentiles, respectively. For the pantoprazole data, horizontal lines above the boxes join genotype groups that are not significantly different from each other as determined by Tukey’s honestly significant difference test after an initial ANOVA. Reproduced from Kearns et al. [37], © The American Society for Pharmacology and Experimental Therapeutics 2010, with permission