PROTONIX is prepared as an enteric-coated tablet so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (C_max) and area under the serum concentration time curve (AUC) increase in a manner proportional to oraÅ? and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oraÅ? or intravenous administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see Metabolism section) with normal liver function receiving an oraÅ? dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (Cm_ax) is 2.4 • g/mL, the time to reach the peak concentration Oma*) is 2.4 h and the total area under the plasma concentration versus time curve (AUC) is 4.8 |j,g-hr/mL. When pantoprazole is given with food, its W^is highly variable and may increase significantly. Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6-14.0 L/h and its apparent volume of distribution is 11.0-23.6L.

Absorption

The absorption of pantoprazole is rapid, with a C_max of 2.5 • g/mL that occurs approximately 2.5 hours after single or multiple oraÅ? 40-mg doses. Pantoprazole is well absorbed; it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of pantoprazole with food may delay its absorption up to 2 hours or longer; however, the C_max and the extent of pantoprazole absorption (AUC) are not altered. Thus, pantoprazole may be taken without regard to timing of meals.

Distribution

The apparent volume of distribution of pantoprazole is approximately 11.0-23.6L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.

Metabolism

Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oraÅ?). The main metabolic pathway is demethylation, by CYP2C19, with subseÄ?uent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (e.g. 3% of Caucasians and African-Americans and 17-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (< 23%) with once daily dosing.

Elimination

After a single oraÅ? or intravenous dose of ¹⁴C-labeled pantoprazole to healthy, normal metabolizer volunteers, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.

Special Populations

Geriatrie

Only slight to moderate inereases in pantoprazole AUC (43%) and C_max (26%) were found in elderly volunteers (64 to 76 years of age) after repeated oraÅ? administration, compared with younger subjeets. No dosage adjustment is recommended based on age. Pediatrie

The pharmacokinetics of pantoprazole have not been investigated in patients <18 years of age. Gender

There is a modest inerease in pantoprazole AUC and C_max in women compared to men. However, weight-normalized clearance values are similar in women and men. No dosage adjustment is needed based on gender (Also see Use in Women).

Renal Impairment

In patients with severe renal impairment, pharmacokinetic parameters for pantoprazole were similar to those of healthy subjeets. No dosage adjustment is necessary in patients with renal impairment or in patients undergoing hemodialysis.

Hepatic Impairment

In patients with mild to moderate hepatic impairment, maximum pantoprazole concentrations inereased only slightly (1.5-fold) relative to healthy subjeets. Although serum half-life values inereased to 7-9 hours and AUC values inereased by 5- to 7-fold in hepatic-impaired patients, these inereases were no greater than those observed in slow CYP2C19 metabolizers, where no dosage freÄ?uency adjustment is warranted. These pharmacokinetic changes in hepatic-impaired patients result in minimal drug accumulation following once daily multiple-dose administration. No dosage adjustment is needed in patients with mild or moderate hepatic impairment. The pharmacokinetics of pantoprazole have not yet been well characterized in patients with severe hepatic impairment. Therefore, the potential for modest drug accumulation (< 21%) when dosed once daily needs to be weighed against the potential for reduced acid control when dosed every other day in these patients.