2010 - Berlin - Germany

PAGE 2010: Applications- Other topics
Jan-Stefan  van der Walt

A population model describing the pharmacokinetics of iv esomeprazole in patients aged 0 to 17 years, inclusive

Jan-Stefan Van Der Walt (1), Joe Standing (1), Mats O Karlsson (1), Per Lundborg (2), Tommy Andersson (2), Kerstin Röhss (2) and Marie Sandström (2)

(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) AstraZeneca, R&D, Sweden

Objectives: A population pharmacokinetic analysis was conducted to describe the steady-state pharmacokinetics of iv esomeprazole and its 5-hydroxy and sulphone metabolites, when given to patients 0 to 17 years old, inclusive.

Methods: Data collected following esomeprazole injection with doses of 0.5mg/kg (age 0-1 month, N=6), 1.0mg/kg (age 1-11 months, N=7), 10mg (age 1-5 years, N=7 and 6-11 years, N=8), 20mg (age 6-11 years, N=8 and 12-17 years, N=6) and 40mg (age 12-17 years, N=8) were used. Blood sampling (1-8 samples) for esomeprazole and its sulphone and 5-hydroxy metabolites were collected in the time window prior to the last dose and until 8.5h after the last dose. Population pharmacokinetic modelling was undertaken in NONMEM VI (FOCE INTER) with emphasis on characterizing the elimination of esomeprazole and metabolites via CYP3A4 and CYP2C19.

Results: The final model consisted of two esomeprazole disposition compartments, and one disposition compartment each for the sulphone and 5-hydroxy metabolites, all with first-order elimination. Post-conceptional age was a significant covariate on the clearance of the sulphone metabolite via CYP2C19 and was modelled as a maturation function (starting at conception and asymptoting in a sigmoidal manner) reaching an adult value at an age of 3-4 years. The CYP3A4 activity was estimated to contribute with 33% to the total clearance of esomeprazole which is in accordance with previous findings (Andersson, 2001). Additional covariates (including body surface area, serum albumin, presence of gastroesophageal reflux disease, arterial vs venous sampling or age/dose group) did not improve the model fit or the predictive performance of the model. The model evaluation by nonparametric bootstrap and visual predictive checks confirmed the model to be robust and to perform well with regard to simulation.

Conclusion: The population pharmacokinetics of iv esomeprazole was well described by the population model and found to be weight- and age-dependent across the age range of 0-17 years, inclusive.

[1] Andersson T, Hassan-Alin M, Hasselgren G, Röhss K. Drug interaction  studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet. 2001; 40(7): 523-37.

Reference: PAGE 19 (2010) Abstr 1905 [www.page-meeting.org/?abstract=1905]
Poster: Applications- Other topics