Nexium

[Esomeprazole]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

Pharmacokinetics

Absorption

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NEXIUM Delayed-Release Capsules contain an enteric-coated pellet formulation of esomeprazole magnesium. After oral administration peak plasma levels (Cmax) occur at approximately 1.5 hours (Tmax).
The Cmax increases proportionally when the dose is increased, and there is a three-fold increase in the area under the plasma concentration-time curve (AUC) from 20 to 40 mg. At repeated once-daily dosing with 40 mg, the systemic bioavailability is approximately 90% compared to 64% after a single dose of 40 mg. The mean exposure (AUC) to esomeprazole increases from 4.32 µmol* hr/ L on day 1 to 11.2 µmol* hr/ L on day 5 after 40 mg once daily dosing. The AUC after administration of a single 40 mg dose of esomeprazole is decreased by 43-53% after food intake compared to fasting condi-tions.

Esomeprazole should be taken at least one hour before meals.
The pharmacokinetic profile of esomeprazole was determined in 36 patients with symptomatic gastroesophageal reflux disease following repeated once daily administration of 20 mg and 40 mg capsules of NEXIUM over a period of five days. The results are shown in the following table:
Pharmacokinetic Parameters of NEXIUM Following Oral Dosing for 5 Days

Parameter NEXIUM NEXIUM 40 mg 20 mg
AUC (µmol* h/ L) 12.6 4.2
Coefficient of variation 42% 59%
Cmax (µmol/ L) 4.7 2.1
Tmax (h) 1.6 1.6
t1/ 2 (h) 1.5 1.2

Values represent the geometric mean, except the Tmax, which is the arithmetic mean.

Distribution

Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2-20 µmol/ L. The apparent volume of distribution at steady state in healthy volunteers
is approximately 16 L.

Metabolism

Esomeprazole is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole lack antisecretory activity. The major part of esomeprazole's metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole, since some 3% of Caucasians and 15-20% of Asians lack CYP2C19 and are termed Poor metabolizers. At steady state, the ratio of AUC in Poor metabolizers to AUC in the rest of the population (Extensive metabolizers) is approximately 2.

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