Proton Pump Inhibitor Use in Infants and Children

A Review of the Recent Literature

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS

Disclosures

Pediatr Pharm. 2019;25(7) 

In This Article

Dose Reduction

It has been suggested that the toxicities seen with PPIs in children may reflect excessive doses and use well beyond the recommended duration of therapy. Current weight-based PPI dosing recommendations have been based on pharmacokinetic and pharmacodynamic studies designed to produce plasma concentrations similar to those of adults receiving standard treatment, which may not represent an appropriate goal for infants and children being treated for GERD or for patients receiving gastric acid suppression as prophylaxis during treatment with non-steroidal anti-inflammatory agents.

The risk for excessive dosing may be heightened in obese children. Several recent papers from Shakhnovich and colleagues, writing for the Best Pharmaceuticals for Children Act Pediatric Trials Network, suggest that obese children require lower doses of pantoprazole than nonobese children to reach effective plasma concentrations.[14–16] In their first paper, the authors conducted a multicenter open-label pharmacokinetic study in 41 obese children and adolescents.[14] The patients, ranging from 6 to 17 years of age, were given a single oral pantoprazole dose of approximately 1.2 mg/kg lean body weight (LBW). All patients had been genotyped for CYP2C19 variants, with the poor metabolizers and ultra-metabolizers excluded from the analysis. Pharmacokinetic parameters were generated using noncompartmental methods and compared to historical data from a previously published study conducted in nonobese patients.

When corrected for a total body weight (TBW)-normalized dose, the apparent clearance (CL/F) and volume of distribution (Vd/F) for pantoprazole were significantly lower in obese children compared to nonobese children (CL/F 0.23 ± 0.13 L/hr/kg versus 0.42 ± 0.27 L/hr/kg, p = 0.03, and Vd/F 0.3 ± 0.1 L/kg versus 0.59 ± 0.36 L/kg, p = 0,008). These changes resulted in significantly greater systemic exposure in the obese patients, as evidenced by higher maximum plasma concentrations (3.52 ± 1.13 mcg/mL versus 2.03 ± 0.92 mcg/mL, p = 0.0001) and area under the concentration-time curve (5.82 ± 3.86 mcg·hr/mL versus 3.45 ± 2.48 mcg·hr/mL, p = 0.04). When corrected for an LBW-normalized dose, those differences were no longer present in the adolescents and were greatly reduced in the children under 12 years of age.

In a subsequent publication, the group used data from their first study to develop a population-based pharmacokinetic model for pantoprazole dosing in obese children and adolescents.[15] Using NONMEM for model development, they generated a two-compartment model that incorporated CYP2C19 genotype and total body weight. The resulting model was used to evaluate different dosing scenarios. The authors found that the currently approved tiered dosing by weight group for oral pantoprazole (20 mg daily of the delayed-release tablets or granules for suspension in children weighing 15 to 39 kg and 40 mg daily in those weighing 40 kg or greater) achieved the desired drug exposure without the need for additional dose escalation for obese patients.

The most recent publication from the group was a prospective study utilizing weight-based pantoprazole dosing with LBW in obese and nonobese children.[16] Sixty-two children between 6 and 17 years of age were enrolled. All patients received a single dose of pantoprazole 1.2 mg/kg calculated with LBW. Serial plasma concentrations were measured over 8 hours. This method compensated for the 50% lower clearance seen in the children with obesity compared to the nonobese children when dosed using TBW. Use of the recommended 1.2 mg/kg LBW, or the tiered approach in the prescribing information for pantoprazole, should minimize excessive dosing and lessen the risk for adverse effects.

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