PRILOSEC (Page 7 of 13)

12.3 Pharmacokinetics

Omeprazole is a time-dependent inhibitor of CYP2C19, resulting in autoinhibition and nonlinear pharmacokinetics. The

systemic exposure increases in a more than dose proportional manner after multiple oral doses of omeprazole. Compared

to the first dose, the systemic exposure (Cmax and AUC0-24h ) at steady state following once a day dosing increased by 61%

and 62%, respectively, compared to after the first dose for the 20 mg dose of PRILOSEC delayed-release capsules and increased by 118% and 175%, respectively, for the 40 mg dose of PRILOSEC delayed-release capsules.

Absorption

PRILOSEC delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma concentrations of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min.

Based on a relative bioavailability study, the AUC and Cmax of PRILOSEC for delayed-release oral suspension were 87% and 88% of those for PRILOSEC delayed-release capsules, respectively.

The bioavailability of omeprazole increases slightly upon repeated administration of PRILOSEC delayed-release capsules.

The systemic exposure (Cmax and AUC) are similar when a 40 mg PRILOSEC delayed-release capsule is administered with and without applesauce. However, administration of a 20 mg PRILOSEC delayed-release capsule with applesauce, results in a mean 25% reduction in Cmax without a significant change in AUC compared to administration without applesauce. The clinical relevance of this finding is unknown.

Distribution

Protein binding is approximately 95%.

Elimination

Metabolism

Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. The major part of its metabolism

is dependent on the polymorphically expressed CYP2C19, responsible for the formation of hydroxyomeprazole, the major

metabolite in plasma. The remaining part is dependent on another specific isoform, CYP3A4, responsible for the

formation of omeprazole sulphone.

Excretion

Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity.

Combination Therapy with Antimicrobials

Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax , AUC0-24 , and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin.

The plasma concentrations of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole.

Table 6: Clarithromycin Tissue Concentrations 2 hours after Dose *
*
Mean ± SD (μg/g)

Tissue

Clarithromycin

Clarithromycin + Omeprazole

Antrum

10.48 ± 2.01 (n = 5)

19.96 ± 4.71 (n = 5)

Fundus

20.81 ± 7.64 (n = 5)

24.25 ± 6.37 (n = 5)

Mucus

4.15 ± 7.74 (n = 4)

39.29 ± 32.79 (n = 4)

Specific Populations

Age: Geriatric Population

The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers.

Age: Pediatric Population

2 to 16 Years of Age

The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age:

Table 7: Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared with Adults
*
Data from single and repeated dose studies. Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules.
Data from a single and repeated dose study. Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules.
Plasma concentration adjusted to an oral dose of 1 mg/kg.

Single or Repeated Oral Dosing/Parameter

Children * ≤ 20 kg
2-5 years
10 mg

Children * > 20 kg

6-16 years

20 mg

Adults (mean 76 kg)

23-29 years (n=12)

Single Dosing

Cmax (ng/mL)

288 (n=10)

495 (n=49)

668

AUC (ng h/mL)

511 (n=7)

1140 (n=32)

1220

Repeated Dosing

Cmax (ng/mL)

539 (n=4)

851 (n=32)

1458

AUC (ng h/mL)

1179 (n=2)

2276 (n=23)

3352

Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children

6 to 16 years of age or adults; AUCs of the latter two groups did not differ [see Dosage and Administration (2)].

1 to 11 Months of Age

A population pharmacokinetics model was used to determine appropriate doses of PRILOSEC in pediatric patients

1 month to less than 1 year of age for treatment (up to 6 weeks) of erosive esophagitis due to acid-mediated GERD. The

model was based on data from 64 children 0.5 month to 16 year of age. Only limited data were available in children below

the age of 1 year. Pediatric doses were simulated in the age group of 1 to 11 month, to achieve comparable omeprazole

exposures with adults following treatment with 20 mg once daily [see Dosage and Administration (2.2)].

Race/Ethnicity

[See Clinical Pharmacology (12.5) ]

Renal Impairment

In patients with chronic renal impairment (creatinine clearance between 10 and 62 mL/min/1.73 m2), the disposition of

omeprazole was very similar to that in healthy subjects, although there was a slight increase in bioavailability. Because

urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the

decreased creatinine clearance. This increase in bioavailability is not considered to be clinically meaningful.

Hepatic Impairment

In patients with chronic hepatic disease classified as Child-Pugh Class A (n=3), B (n=4) and C (n=1), the bioavailability

increased to approximately 100% compared to healthy subjects, reflecting decreased first-pass effect, and the plasma

half-life of the drug increased to nearly 3 hours compared with the half-life in healthy subjects of 0.5 to 1 hour. Plasma

clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in healthy subjects [see Dosage and

Administration (2.1), Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Omeprazole on Other Drugs

Omeprazole is a time-dependent inhibitor of CYP2C19 and can increase the systemic exposure of co-administered drugs

that are CYP2C19 substrates. In addition, administration of omeprazole increases intragastric pH and can alter the

systemic exposure of certain drugs that exhibit pH-dependent solubility.

Antiretrovirals

For some antiretroviral drugs, such as rilpivirine, atazanavir and nelfinavir, decreased serum concentrations have been

reported when given together with omeprazole [see Drug Interactions (7)].

Rilpivirine: Following multiple doses of rilpivirine (150 mg, daily) and omeprazole (20 mg, daily), AUC was decreased

by 40%, Cmax by 40%, and Cmin by 33% for rilpivirine.

Nelfinavir: Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was

decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8.

Atazanavir: Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before

atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%.

Saquinavir: Following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40

mg daily co-administered days 11 to 15.

AUC was increased by 82%, Cmax by 75%, and Cmin by 106%. The mechanism behind this interaction is not fully

elucidated. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use

with PRILOSEC.

Clopidogrel

In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together.

Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period.

In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction [see Warnings and Precautions (5.6),Drug Interactions (7)].

Mycophenolate Mofetil

Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA [see Drug Interactions (7)].

Cilostazol

Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy

subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. The Cmax and AUC of one of the active metabolites, 3,4- dihydro-cilostazol, which has 4-7 times the activity of cilostazol, were increased by

29% and 69%, respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of

cilostazol and the above mentioned active metabolite [see Drug Interactions (7)].

Diazepam

Concomitant administration of omeprazole 20 mg once daily and diazepam 0.1 mg/kg given intravenously resulted in

27% decrease in clearance and 36% increase in diazepam half-life [see Drug Interactions (7)].

Digoxin

Concomitant administration of omeprazole 20 mg once daily and digoxin in healthy subjects increased the bioavailability

of digoxin by 10% (30% in two subjects) [see Drug Interactions (7)].

Effect of Other Drugs on Omeprazole

Voriconazole

Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in

more than doubling of the omeprazole exposure. When voriconazole (400 mg every 12 hours for one day, followed by

200 mg once daily for 6 days) was given with omeprazole (40 mg once daily for 7 days) to healthy subjects, the steady-state Cmax and AUC0-24 of omeprazole significantly increased: an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90%

CI: 3.3, 4.4), respectively, as compared to when omeprazole was given without voriconazole [see Drug Interactions (7)].

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