Omeprazole dose recommendation in pediatric patients aged 1-11 months with erosive esophagitis
Carl-Christer Johansson, Mohammad Niazi, Tommy Andersson, Ulrika Wählby-Hamrén
Quantitative Clinical Pharmacology, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Gothenburg, Sweden
Objectives: Omeprazole (PRILOSEC) 20mg once daily is approved in the US for adults with gastroesophageal reflux disease and erosive esophagitis. The label includes children >1 year of age, with a body weight adjusted dosing algorithm. A PRILOSEC sachet formulation was developed for infants and the present analysis aimed to support the dose recommendation of omeprazole in children aged 1-11 months with erosive esophagitis.
Methods: Due to the very limited PK data available (n=4) in the target population, 1-11 months, an integrative approach was taken to utilize PK and PD data from: adults, older children and for omeprazole1,2 and esomeprazole3,4. Exposure-response (AUC-acid secretion) across these populations and products were assessed for justification of bridging on PK alone. A population PK model was developed based on available omeprazole pediatric data and allometric scaling of CL/F and V/F was assumed a priori. The age dependent maturation of CL was assessed on iv omeprazole pediatric data. Simulations with the final model were used to explore dosing options in children 1-11 months, aiming for a similar exposure (AUC) to the adult 20mg once daily omeprazole dose.
Results: The exposure-response relationship was shown to be similar in adults and children for both omeprazole and esomeprazole, thus supporting bridging of doses from adults based on PK alone. Simulations were performed based on the developed population PK model; a one compartment model with first order absorption and lag-time. The simulation model further included the maturation function on CL and a relative increase in oral bioavailability in children below 1 year that has previously been reported5. Simulated exposures (AUC) were over all in good agreement with the exposure derived by non-compartmental analysis. The selected doses, in children <1 year, matching the exposure in adults receiving 20 mg of omeprazole were: 2.5mg (3<5kg), 5mg (5<10 kg) and 10mg (≥ 10kg).
Conclusions: The suggested omeprazole doses (2.5, 5 and 10 mg) in children 1-11 months with erosive esophagitis are likely to demonstrate efficacy and minimize the risk that the exposure will reach levels leading to safety concerns. The PRILOSEC label was recently updated to include the presented dose recommendation for children below 1 year of age.
References:
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