NEXIUM (Page 8 of 12)

12.3 Pharmacokinetics

Absorption

NEXIUM delayed-release capsules and NEXIUM for delayed-release oral suspension. showed similar bioavailability after a single dose (40 mg) administration in 94 healthy male and female subjects under fasting conditions. After oral administration, peak plasma levels (C max ) of esomeprazole occur at approximately 1.5 hours (T max ). The C max 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 micromol*hr/L on Day 1 to 11.2 micromol*hr/L on Day 5 after 40 mg once daily dosing.

The AUC after administration of a single 40 mg dose of NEXIUM delayed-release capsules is decreased by 43% to 53% after food intake compared to fasting conditions [see Dosage and Administration (2.3)]. The pharmacokinetics of esomeprazole in adult patients with symptomatic GERD following repeated once daily administration of 20 mg and 40 mg NEXIUM delayed-release capsules over a period of five days are shown in Table 6:

Table 6: Geometric Mean (95% CI) Pharmacokinetic Parameters of Esomeprazole on Day 5 Following Once Daily Dosing of NEXIUM Delayed-Release Capsules in Adult Patients with Symptomatic GERD
*
Values represent the geometric mean, except the T max, which is the arithmetic mean; CV = Coefficient of variation

NEXIUM delayed-release capsules

Parameter * (CV)

40 mg once daily

(n=36)

20 mg once daily

(n=36)

AUC (micromol·h/L)

12.6 (42%)

4.2 (59%)

C max (micromol/L)

4.7 (37%)

2.1 (45%)

T max (hours)

1.6

1.6

t 1/2 (hours)

1.5

1.2

Esomeprazole 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 esomeprazole. Compared to the first dose, the systemic exposure (C max and AUC 0-24h ) at steady state following once a day dosing increased by 43% and 90%, respectively, compared to after the first dose for the 20 mg dose and increased by 95% and 159%, respectively, for the 40 mg dose.

Distribution

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

Elimination

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.

Excretion

The plasma elimination half-life of esomeprazole is approximately 1 to 1.5 hours. Less than 1% of parent drug is excreted in the urine. Approximately 80% of an oral dose of esomeprazole is excreted as inactive metabolites in the urine, and the remainder is found as inactive metabolites in the feces.

Combination Therapy with Amoxicillin and Clarithromycin

NEXIUM delayed-release capsules 40 mg once daily was given in combination with amoxicillin 1000 mg twice daily and clarithromycin 500 mg twice daily for 7 days to 17 healthy male and female subjects. The mean steady state AUC and C max of esomeprazole increased by 70% and 18%, respectively during combination therapy compared to treatment with NEXIUM alone. The observed increase in esomeprazole exposure during co-administration with amoxicillin and clarithromycin is not expected to be clinically relevant.

The pharmacokinetic parameters for amoxicillin and clarithromycin were similar during combination therapy and administration of each drug alone. However, the mean AUC and C max for 14-hydroxyclarithromycin increased by 19% and 22%, respectively, during combination therapy compared to treatment with clarithromycin alone. This increase in exposure to 14-hydroxyclarithromycin is not considered to be clinically relevant.

Specific Populations

Geriatric Patients

The AUC and C max values of esomeprazole were slightly higher (25% and 18%, respectively) in the elderly as compared to younger subjects at steady state. This increase in exposure is not considered clinically relevant.

Pediatric Patients

1 Month to 11 Months of Age

The pharmacokinetic parameters following repeated dose administration of esomeprazole magnesium 1 mg/kg once daily for 7 to 8 days in 1 month to 11-month-old infants with GERD are summarized in Table 7.

Table 7: Summary of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of Oral Esomeprazole Magnesium for 7 to 8 Days in 1 Month to 1 Year Old Infants with GERD
*
Geometric mean
Median

Parameter

Esomeprazole Magnesium 1 mg/kg Orally Once Daily

AUC (micromol·h/L) (n=7) *

3.51

C ss,,max (micromol/L) (n=15) *

0.87

t ½ (h) (n=8) *

0.93

t max (h) (n=15)

3.0

Subsequent pharmacokinetic simulation analyses showed that for pediatric patients 1 month to 11 months of age, a dosage regimen of 2.5 mg once daily (body weight 3 to 5 kg), 5 mg once daily (body weight more than 5 to 7.5 kg) and 10 mg once daily for (body weight more than 7.5 to 12 kg) would achieve comparable steady-state plasma exposures (AUC) to that observed with 10 mg once daily in patients 1 year to 11 year of age and 20 mg once daily in patients 12 years to 18 years of age, as well as adults.

Apparent clearance (CL/F) increases with age in pediatric patients with GERD from 1 month to 2 years of age.

1 Year to 11 Years of Age

The pharmacokinetics of esomeprazole were studied in pediatric patients with GERD aged 1 year to 11 years. Following once daily dosing with NEXIUM for delayed-release oral suspension for 5 days, the total exposure (AUC) for the 10 mg dosage in patients aged 6 years to 11 years was similar to that seen with the 20 mg dosage in adults and adolescents aged 12 years to 17 years. The total exposure for the 10 mg dosage in patients aged 1 year to 5 years was approximately 30% higher than the 10 mg dosage in patients aged 6 years to 11 years. The total exposure for the 20 mg dosage in patients aged 6 years to 11 years was higher than that observed with the 20 mg dosage in patients aged 12 years to 17 years and adults, but lower than that observed with the 40 mg dosage in 12 to 17 year-olds and adults. See Table 8.

Table 8: Summary of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of NEXIUM for Delayed-Release Oral Suspension for 5 Days in 1 Year to 11 Year Old Patients with GERD
*
Geometric mean
Arithmetic mean

Parameter

NEXIUM For Delayed-Release Oral Suspension

1 Year to 5 Years

6 Years to 11 Years

10 mg once daily (N=8)

10 mg once daily (N=7)

20 mg once daily (N=6)

AUC (micromol h/L) *

4.83

3.70

6.28

C max (micromol/L) *

2.98

1.77

3.73

t max (h)

1.44

1.79

1.75

t ½λz (h) *

0.74

0.88

0.73

Cl/F (L/h) *

5.99

7.84

9.22

12 Years to 17 Years of Age

The pharmacokinetics of NEXIUM were studied in 28 adolescent patients with GERD aged 12 to 17 years inclusive, in a single center study. Patients were randomized to receive NEXIUM 20 mg or 40 mg once daily for 8 days. Mean C max and AUC values of esomeprazole were not affected by body weight or age; and more than dose-proportional increases in mean C max and AUC values were observed between the two dose groups in the study. Overall, NEXIUM pharmacokinetics in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD. See Table 9.

Table 9: Comparison of Esomeprazole Pharmacokinetic Parameters Following Once Daily Dosing of NEXIUM Delayed-Release Capsules in Pediatric Patients 12 Years to 17 Years with GERD and Adults with Symptomatic GERD *
*
Data obtained from two independent studies.

Parameter

NEXIUM Delayed-Release Capsules

12 Years to 17 Years (N=28)

Adults (N=36)

20 mg once daily

for 8 days

40 mg once daily

for 8 days

20 mg once daily

for 5 days

40 mg once daily

for 5 days

AUC (micromole h/L)

3.65

13.86

4.2

12.6

C max (micromol/L)

1.45

5.13

2.1

4.7

t max (h)

2.00

1.75

1.6

1.6

t ½λz (h)

0.82

1.22

1.2

1.5

Data presented are geometric means for AUC, C max and t ½λz , and median value for t max .

Male and Female Patients

The AUC and C max values of esomeprazole were slightly higher (13%) in females than in males at steady state when dosed orally. This increase in exposure is not considered clinically relevant.

Patients with Renal Impairment

The pharmacokinetics of NEXIUM in patients with renal impairment are not expected to be altered relative to healthy subjects as less than 1% of esomeprazole is excreted unchanged in urine.

Patients with Hepatic Impairment

The steady state pharmacokinetics of esomeprazole obtained after administration of NEXIUM delayed-release capsules 40 mg orally once daily to patients with mild (Child-Pugh Class A, n=4), moderate (Child-Pugh Class B, n=4), and severe (Child-Pugh Class C, n=4) hepatic impairment were compared to those obtained in 36 male and female GERD patients with normal liver function. In patients with mild and moderate hepatic impairment, the AUCs were within the range that could be expected in patients with normal liver function. In patients with severe hepatic impairment the AUCs were 2 to 3 times higher than in the patients with normal liver function [see Use in Specific Populations (8.6)].

Drug Interaction Studies

Effect of Esomeprazole/Omeprazole on Other Drugs

In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1 and 3A4.

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%, C max by 40%, and C min by 33% for rilpivirine [see Contraindications (4)] .

Nelfinavir:

Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min 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%, C max by 96%, and C min 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. The AUC was increased by 82%, C max by 75%, and C min by 106%. The mechanism behind this interaction is not fully elucidated.

Clopidogrel

In a crossover study, healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day as the maintenance dosage for 28 days) alone and with esomeprazole (40 mg orally once daily at the same time as clopidogrel) for 29 days. Exposure to the active metabolite of clopidogrel was reduced by 35% to 40% over this time period when clopidogrel and esomeprazole were administered together. Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation was related to the change in the exposure to clopidogrel active metabolite [see Warnings and Precautions (5.7) and 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 C max 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 C max and AUC of cilostazol by 18% and 26% respectively. The C max and AUC of one of the active metabolites, 3,4-dihydro-cilostazol, which has 4 to 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

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Increased plasma levels of diazepam were observed 12 hours after dosing and onwards. However, at that time, the plasma levels of diazepam were below the therapeutic interval, and thus this interaction is unlikely to be of clinical relevance.

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)].

Other Drugs

Concomitant administration of esomeprazole and either naproxen (non-selective NSAID) did not identify any clinically relevant changes in the pharmacokinetic profiles of these NSAIDs.

Effect of Other Drugs on Esomeprazole/Omeprazole

St. John’s Wort

In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolizers (C max and AUC both decreased by 38%) and extensive metabolizers (C max and AUC decreased by 50% and 44%, respectively) [see Drug Interactions (7)] .

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 C max and AUC 0-24 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)] .

Other Drugs

Co-administration of esomeprazole with oral contraceptives, diazepam, phenytoin, quinidine, naproxen (non-selective NSAID) did not seem to change the pharmacokinetic profile of esomeprazole.

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