Mohammed Hassan-Alin

Pharmacokinetic Studies with Esomeprazole, the (S)-Isomer of Omeprazole

AbstractThis article reviews the pharmacokinetics of esomeprazole, the (S)-isomer of the proton pump inhibitor (PPI) omeprazole. Esomeprazole is the first single isomer PPI developed for the treatment of patients with acid-related diseases. In vitro experiments in human liver microsomes demonstrated that the formation of the hydroxy and 5-O-desmethyl metabolites of esomeprazole is via cytochrome P450 (CYP) 2C19, whereas that of the sulphone metabolite is via CYP3A4. The formation rate of the hydroxy metabolite from esomeprazole is lower than for (R)-omeprazole, but that of the 2 other metabolites is higher, demonstrating stereoselective metabolism. The sum of the intrinsic clearances of all 3 metabolites for esomeprazole was one-third of that for (R)-omeprazole, suggesting lower clearance of esomeprazole in vivo.In vivo investigations demonstrated that esomeprazole is chirally stable after administration. Esomeprazole is 97% bound to plasma proteins. In normal (extensive) metabolisers with regard to CYP2C19, esomeprazole is metabolised more slowly than omeprazole, resulting in a higher area under the concentration-time curve (AUC) after administration of the same dose. This is more pronounced after repeated administration rather than after a single dose. In poor metabolisers, the AUC is lower for esomeprazole than for omeprazole, contributing to less overall interindividual variability for esomeprazole than for omeprazole.In general, esomeprazole and omeprazole are subject to the same metabolic transformations. Almost complete recoveries were reported and the ratio between urinary and faecal excretion is about 4: 1 for both compounds. The dose-dependent increase in AUC of esomeprazole with repeated administration results from a combination of decreased first-pass elimination and decreased systemic clearance. Patients with gastro-oesophageal reflux disease exhibit a pharmacokinetic pattern similar to that in healthy individuals, whereas elderly individuals exhibited a slightly lower metabolism rate.Patients with a severe deficit in their liver function had a lower rate of metabolism, as would be expected, whereas those with mild to moderate liver disease did not exhibit any alteration in the pharmacokinetics. The pharmacokinetics of esomeprazole in individuals with impaired renal function is unlikely to differ from that in healthy individuals. A slight sex difference in the pharmacokinetics of esomeprazole was demonstrated in that the AUC and peak plasma drug concentration were slightly, but not statistically significantly, higher in females than in males.

Pharmacokinetics and pharmacodynamics of esomeprazole, the S‐isomer of omeprazole

Esomeprazole, the S‐isomer of omeprazole, is the first proton pump inhibitor developed as a single isomer for the treatment of acid‐related diseases.

Drug Interaction Studies with Esomeprazole, the (S)-Isomer of Omeprazole

Esomeprazole, the (S)-isomer of omeprazole, is the first proton pump inhibitor (PPI) developed as a single isomer for the treatment of patients with acid related diseases. Because of the extensive use of PPIs, the documentation of the potential for drug interactions with esomeprazole is of great importance.Altered absorption or metabolism are 2 of the major mechanisms for drug-drug interactions. Since intragastric pH will increase with esomeprazole treatment, it can be hypothesised that the absorption of drugs with pH-sensitive absorption (e.g. digoxin and ketoconazole) may be affected.Esomeprazole does not seem to have any potential to interact with drugs that are metabolised by cytochrome P450 (CYP) 1A2, 2A6, 2C9, 2D6 or 2E1. In drug interaction studies with diazepam, phenytoin and (R)-warfarin, it was shown that esomeprazole has the potential to interact with CYP2C19. The slightly altered metabolism of cisapride was also suggested to be the result of inhibition of a minor metabolic pathway for cisapride mediated by CYP2C19. Esomeprazole did not interact with the CYP3A4 substrates clarithromycin (2 studies) or quinidine. Since the slightly increased area under the concentration-time curve (AUC) of cisapride could be explained as an inhibition of CYP2C19, the data on these 3 CYP3A4 substrates indicate that esomeprazole does not have the potential to inhibit this enzyme.The minor effects reported for diazepam, phenytoin, (R)-warfarin, and cisapride are unlikely to be of clinical relevance. Clarithromycin interacts with the metabolism of esomeprazole resulting in a doubling of the AUC of esomeprazole. The increased plasma concentrations of esomeprazole are unlikely to have any safety implications.It can be concluded that the potential for drug-drug interactions with esomeprazole is low, and similar to that reported for omeprazole.

Pharmacokinetic Study of Esomeprazole in the Elderly

ObjectiveEsomeprazole is the first proton pump inhibitor to be developed as an optical isomer for the treatment of patients with acid-related diseases. The aim of this study was to examine the pharmacokinetics and tolerability of esomeprazole in the elderly, relative to middle-aged patients with gastro-oesopha-geal reflux disease (GORD).DesignNonblinded single-centre pharmacokinetic study with historical control group.Patients and Participants14 healthy elderly volunteers [mean age 74 (range 71 to 80) years].MethodsParticipants received treatment with esomeprazole 40mg once daily for 5 days, with 24-hour blood sampling on days 1 and 5. The total area under the plasma concentration-time curve (AUC∞), maximum plasma drug concentration (Cmax), terminal elimination half-life (t1/2z) and time to Cmax (tmax) were determined for the parent drug and its hydroxy and sulphone metabolites. AUC∞ and Cmax data were compared with those in an historical group of 36 middle-aged patients [mean age 45 (range 29 to 58) years] with GORD, treated with an identical dosage of esomeprazole for 5 days.ResultsA total of 13 volunteers completed the study. On day 5, the mean plasma AUC∞ of esomeprazole was 16.0 µmol · h/L, Cmaxwas 5.6 µmol/L, tmax was 1.5 hours and t1/2z was 1.7 hours. The AUC∞ and Cmax values for the parent drug were 2- and 1.5-fold higher on day 5 compared with day 1. AUC∞ and Cmax values for the sulphone metabolite increased to a slightly greater extent, and values for the hydroxy metabolite were unchanged. Ratios of the AUC∞ and Cmax values between elderly volunteers and patients with GORD were 1.25 [95% confidence interval (CI) 0.94, 1.67] and 1.18 (0.91, 1.52), respectively. Esomeprazole was well tolerated and there were no safety concerns.ConclusionsThe AUC∞ and Cmax values in the elderly were not significantly different from those obtained in a group of middle-aged patients. The difference for AUC∞ was 25% (95% CI −6% to +67%). Esomeprazole has a wide therapeutic window and our results do not indicate that dosage adjustment should be necessary in the elderly.

Pharmacokinetic study of esomeprazole in patients with hepatic impairment

Objective To evaluate the pharmacokinetics and safety of esomeprazole (Nexium), the S-isomer of omeprazole, after repeated oral dosing in patients with hepatic impairment. Design Single-centre, open-label one-way study. Methods Twelve patients (aged 40–60 years) with mild to severe hepatic impairment received once-daily oral esomeprazole 40 mg for 5 days. Serial blood samples were drawn up to 24 h post-dose on day 5 to determine plasma levels of esomeprazole and its metabolites. Pharmacokinetic parameters were compared with an historical control group of 36 gastro-oesophageal reflux disease (GORD) patients (aged 29–58 years) with normal hepatic function. Results Esomeprazole was absorbed rapidly (mean maximum plasma concentration (Cmax) 6.1 μmol/l, mean time to Cmax (tmax) 1.9 h) and eliminated rapidly (mean plasma elimination half-life (t1/2) 2.1 h). Elimination of its pharmacologically inactive sulphone and hydroxy metabolites was more gradual. Patients with mild hepatic impairment had area under the plasma concentration–time curve during the dosage interval (AUCτ) and t1/2 values largely within the range of the control group. In patients with moderate hepatic impairment, t1/2 values were similar and AUCτ was slightly higher than in controls, whereas both parameters were increased in patients with severe hepatic impairment. The mean ratios of esomeprazole AUCτ, Cmax and t1/2 values in patients with and without hepatic impairment were 1.8, 1.3 and 1.3, respectively. Conclusions The steady-state pharmacokinetics of esomeprazole were not altered substantially by mild or moderate hepatic impairment; however, plasma levels of esomeprazole were elevated in severe cases. Thus, dose adjustment appears unwarranted in mild or moderate hepatic impairment, but may be required in some severely impaired patients. Esomeprazole was tolerated well across the spectrum of hepatic impairment.

Lack of Pharmacokinetic Interaction between Esomeprazole and the Nonsteroidal Anti-Inflammatory Drugs Naproxen and Rofecoxib in Healthy Subjects

AbstractBackground: We investigated the potential interactions between esomeprazole and a non-selective nonsteroidal anti-inflammatory drug (NSAID; naproxen) or a cyclo-oxygenase (COX)-2-selective NSAID (rofecoxib) in healthy subjects. Methods: Two studies of identical randomised, open, three-way crossover design were conducted. Subjects (n = 32 for both studies) were to receive 1 week’s treatment with esomeprazole 40mg once daily (studies A and B), naproxen 250mg twice daily (study A), rofecoxib 12.5mg once daily (study B), and esomeprazole in combination with naproxen (study A) or rofecoxib (study B). Study periods were separated by a 2-week washout period. Results: On day 7 of dosing, the ratios (and 95% CIs) for the area under the plasma concentration-time curve during the dosing interval (AUCτ) and observed maximum plasma concentration (Cmax) of esomeprazole and NSAID combination/NSAID alone were 0.98 (0.94, 1.01) and 1.00 (0.97, 1.04), respectively, for study A, and 1.15 (1.06, 1.24) and 1.14 (1.02, 1.28), respectively, for study B. The ratios (and 95% CIs) for AUCτ and Cmax of esomeprazole and NSAID combination/esomeprazole alone were 0.96 (0.89, 1.03) and 0.92 (0.85, 1.00), respectively, for study A, and 1.05 (0.96, 1.15) and 1.05 (0.94, 1.18), respectively, for study B. All treatments were well tolerated during the study period. Conclusion: Naproxen and rofecoxib do not interact with esomeprazole, and esomeprazole does not affect the pharmacokinetics of naproxen or rofecoxib. These findings indicate that esomeprazole can be used in combination with NSAIDs without the risk of a pharmacokinetic interaction.

Intravenous Esomeprazole 40mg is Effective for the Control of Intragastric Acid Levels Whether Given as a 3-Minute Injection or a 30-Minute Infusion.

AbstractBackground: An intravenous (IV) formulation of esomeprazole has been developed as an alternative to oral administration. To meet the needs of different clinical situations it would be preferable if an IV dose could be administered as either an injection or an infusion, while producing similar effects. Aim: To compare the effects of IV esomeprazole 40mg given as a 3-minute injection or a 30-minute infusion on intragastric pH during single and repeated once-daily dosing in healthy subjects. Methods: In this single-centre, double-blind, double-dummy, randomised, two-way crossover study, subjects were randomised to receive either a 3-minute IV injection or a 30-minute IV infusion of esomeprazole 40mg. Both regimens were given once daily for 10 days. After a washout period of at least 13 days, subjects were crossed over to the other treatment. Intragastric pH monitoring was performed on days 1 and 10. Blood samples were also taken throughout days 1 and 10. Results: Data were available from 41 subjects. Time with intragastric pH >4 was 3.1h/24h at baseline, increasing to almost 8h in association with IV esomeprazole injection or infusion on day 1, and to >13h on day 10. Geometric mean time with pH >4/24h ratios (injection/infusion) were 0.99 on day 1 and 1.03 on day 10. Mean esomeprazole AUC values were approximately 15% higher with the injection than the infusion, but 90% CI limits for geometric mean AUC ratios ranged from 1.07 to 1.23, indicating bioequivalence. Conclusions: IV esomeprazole 40mg provides similarly potent acid control whether administered by injection or infusion.

Lack of drug-drug interaction between esomeprazole and rofecoxib in healthy subjects

deterioration dining withdrawal of PPI treatment. Conclusions: Chinese-GERDQ was easytomndersrand, internally consistent and reproducible. It predicted global symptom change, and the symptom seventy scores correlated negatively with quality of life. It could be used m epidemiologieal studies to assess the t~ceqnancy and severity of GERD in patient populations and in interventional studies of GERD.