Esomeprazole magnesium delayed-release capsules. 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 ) 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 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 magnesium delayed-release capsules is decreased by 43% to 53% after food intake compared to fasting conditions [see Dosage and Administration (2.3)]. The pharmacokinetic of esomeprazole in adult patients with symptomatic GERD following repeated once daily administration of 20 mg and 40 mg esomeprazole magnesium delayed-release capsules over a period of five days are shown in Table 6.
1. Values represent the geometric mean, except the T max , which is the arithmetic mean; CV = Coefficient of variation
|Parameter 1 (CV)||Esomeprazole Magnesium Delayed-Release Capsules|
|40 mg once daily (n=36)||20 mg once daily (n=36)|
|AUC (µmol∙h/L)||12.6 (42%)||4.2 (59%)|
|C max (µmol/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 (Cmax and AUC0-24h) 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.
Esomeprazole is 97% bound to plasma proteins. Plasma protein binding is constant over the concentration range of 2 to 20 mol/L. The apparent volume of distribution at steady state in healthy subjects is approximately 16 L.
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.
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 Clarithromyc in
Esomeprazole magnesium delayed-release capsules 40 mg once daily was given in combination with amoxicillin 1,000 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 triple combination therapy compared to treatment with esomeprazole 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.
The AUC and C max values 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.
12 years to 17 Years of Age
The pharmacokinetics of esomeprazole magnesium delayed-release capsules were studied in 28 adolescent patients with GERD aged 12 to 17 years inclusive, in a single center study. Patients were randomized to receive esomeprazole magnesium delayed-release capsules 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, esomeprazole magnesium delayed-release capsules in adolescent patients aged 12 to 17 years were similar to those observed in adult patients with symptomatic GERD. See Table 9.
1. Data were obtained from two independent studies.
|Esomeprazole Magnesium Delayed-Release Capsules|
|12 Years to 17 Years (N=28)||Adults (N=36)|
|Parameter||20 mg once daily for 8 days||40 mg once daily for 8 days||20 mg once daily for 8 days||40 mg once daily for 8 days|
|C max (µmol/L)||1.45||5.13||2.1||4.7|
|t max (h)||2.00||1.75||1.6||1.6|
|t ½z (h)||0.82||1.22||1.2||1.5|
|Data presented are geometric means for AUC, C max and t ½z , and median value for t max .|
Male and Female Patients
The AUC and Cmax 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 esomeprazole magnesium 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 esomeprazole magnesium 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.
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 [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%, 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. The AUC was increased by 82%, Cmax by 75%, and Cmin by 106%. The mechanism behind this interaction is not fully elucidated.
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) ] .
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)] .
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 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) ] .
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.
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) ] .
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 (Cmax and AUC both decreased by 38%) and extensive metabolizers (Cmax and AUC decreased by 50% and 44%, respectively) [see Drug Interactions ( 7) ] .
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) ] .
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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