Abstract:The population pharmacokinetics of pantoprazole was characterized in pediatric patients from birth to 16 years using NONMEM and evaluated via bootstrap and predictive check. Data were described using a 2-compartment model with a typical parameterized in terms of clearance (CL) (95% CI) of 1.93 L per hour (1.53, 2.61), given the reference covariates (female, full term, extensive/unknown CYP2C19 metabolizer status, non-African American, 10 kg weight, intravenous or tablet administration). Pantoprazole pharmacoki… Show more
“…Figure 3 illustrates the apparent oral clearance (CL/F) of pantoprazole in patients from the neonatal period through adolescence [35]. These data were derived from a series of clinical trials submitted to the US FDA for approval and depict information from subjects whose CYP2C19 genotype would predict an extensive metabolizer phenotype.…”
Section: Pharmacokinetics and The Disposition Of Ppis In Infants And mentioning
confidence: 99%
“…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 .…”
Section: Pharmacokinetics and The Disposition Of Ppis In Infants And mentioning
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.
“…Figure 3 illustrates the apparent oral clearance (CL/F) of pantoprazole in patients from the neonatal period through adolescence [35]. These data were derived from a series of clinical trials submitted to the US FDA for approval and depict information from subjects whose CYP2C19 genotype would predict an extensive metabolizer phenotype.…”
Section: Pharmacokinetics and The Disposition Of Ppis In Infants And mentioning
confidence: 99%
“…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 .…”
Section: Pharmacokinetics and The Disposition Of Ppis In Infants And mentioning
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.
“…Recent studies in children have also demonstrated the importance of CYP2C19 variants [60][61][62]. The clearance of pantoprazole was estimated in pediatric patients from birth to 16 years and was 60% lower in PMs compared to EMs [63]. Our group compared drug levels following a single dose of conventionally dosed lansoprazole with CYP2C19 genotype/metabolizer phenotype in 56 children with GERD and found a direct relationship between CYP2C19 diplotype and lansoprazole concentration [64].…”
Asthma causes enormous suffering and cost for children in the US and around the world [1-3]. Comorbid gastroesophageal reflux disease (GERD) makes asthma management more difficult due to increased symptoms. Proton pump inhibitor (PPI) drugs are effective at improving to GERD symptoms, however they have demonstrated only modest and variable effects on asthma control in the setting of co-morbid GERD. Importantly, PPI metabolism and efficacy depend on CYP2C19 genotype. The Genotype Tailored Treatment of Symptomatic Acid Reflux in Children with Uncontrolled Asthma (GenARA) study is a randomized, double-blind, placebo-controlled trial to determine if genotype-tailored PPI dosing improves asthma symptoms among children with inadequately controlled asthma and GERD symptoms. This study has an innovative design to both assess the efficacy of genotype-tailored PPI dosing and perform pharmacokinetic modeling of the oral PPI Lansoprazole. Children ages 6-17 years old with clinician-diagnosed asthma and mild GERD symptoms will submit a saliva sample for CYP2C19 genotyping. Participants will undergo a two-step randomization to: (1) genotype-tailored versus conventional dosing of open-label oral lansoprazole for pharmacokinetic modeling, and (2) genotype-tailored lansoprazole daily versus placebo for 24 weeks to determine the effect of genotype-tailored PPI dosing on asthma control. Measures of asthma control, spirometry, and nasal washes during acute illnesses will be collected at 8-week intervals throughout the study. GenARA will better define the effects of CYP2C19 genotype on the dose response of lansoprazole in children and adolescents and assess if a novel dosing regimen improves GERD and asthma control. Tang et al.
“…In children aged 6-16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults [142]. Simulations indicated that the 1.2-mg/kg dose provides the best comparison to adults [143]. Pantoprazole is generally well tolerated in infants and children aged 1 month through < 6 years; compared with adults receiving pantoprazole 40 mg, exposure obtained with the 1.2-mg/kg dose was similar [144].…”
Section: H²-receptor Antagonists and Proton Pump Inhibitorsmentioning
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