Population Pharmacokinetic Modelling of Esomeprazole Nonlinearity
Joseph F Standing (1), Marie Sandstr÷m (2), Tommy Andersson (2), Kerstin R÷hss (2), Mats O Karlsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Sweden; (2) AstraZeneca Ltd., Sweden.
Objectives: Esomeprazole is a proton pump inhibitor that binds covalently to H+,K+,ATPase. The pharmacokinetics of esomeprazole are non-linear, with decreased CL occurring with increasing time and dose . This nonlinearity is thought to arise from CYP2C19 autoinhibition . A population pharmacokinetic description of this nonlinearity is presented, whereby the effect of repeated, and increased dosing on clearance was investigated.
Methods: Data from a previously published non-compartmental analysis were used . Healthy volunteers (n=25) received 40mg esomeprazole by 30min intravenous infusion. After a washout, subjects then received 5 days of once-daily oral esomeprazole 40mg, followed by a second intravenous dose on day 6. Rich blood sampling for esomeprazole and two metabolites (sulphone and hydroxy) were collected until 24hr post-dose for both intravenous doses and the first and last oral dose.
Population pharmacokinetic modelling was undertaken in NONMEM VI (FOCE INTER), initially using the intravenous esomeprazole data, then adding the oral data. One and two compartment disposition models were tested, along with autoinhibition models derived from Michaelis-Menten and saturable turnover behaviour to describe CL.
Results: The final model consisted of two disposition compartments with a linear component of CL, along with a second saturable elimination pathway. This pathway was best represented by a saturable turnover model, the parameters being a zero-order synthesis rate (Ksyn), second order binding constant (Kon) and pathway degradation (Kdeg). Loss from the depot compartment by this route was also allowed, and a maximal bioavailability (when this would be saturated) was estimated.
Basic goodness-of-fit and model derived versus non-compartmental AUC at first and steady-state doses showed the model described the time-dependent AUC well. For a typical 70kg individual the linear component of CL was 7.4 L/hr and Vss 15.5 L. Kdeg was estimated to be 0.0129/hr (i.e. t1/2 of 54hrs), which predicts the steady-state decrease in CL taking around 7 days.
Conclusions: The nonlinearity in esomeprazole clearance with time has been described. Future work will include metabolite concentrations and a larger dose-range to further investigate non-linearity.
. Hassan-Alin, M, et al. Eur J Clin Pharmacol 2000;56:665-70.
. Andersson, T, et al. Clin Pharmacokinet 2001;40:411-26.