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Drugs

, Volume 48, Issue 3, pp 404–430 | Cite as

Lansoprazole

A Reappraisal of its Pharmacodynamic and Pharmacokinetic Properties, and its Therapeutic Efficacy in Acid-Related Disorders
  • Caroline M. Spencer
  • Diana Faulds
Drug Evaluation

Abstract

Synopsis

Lansoprazole is a benzimidazole derivative that effectively decreases gastric acid secretion, regardless of the primary stimulus, via inhibition of gastric H+,K+-adenosine triphosphatase (ATPase). It provides effective symptom relief and healing of peptic ulcer and reflux oesophagitis after 4 to 8 weeks of therapy and appears to prevent recurrence of lesions when administered as maintenance therapy.

When administered at therapeutic dosages, lansoprazole produced higher healing rates than ranitidine or famotidine in patients with duodenal and gastric ulcers. Lansoprazole heals duodenal ulcers more rapidly than ranitidine or famotidine. Relief of ulcer symptoms in lansoprazole recipients is at least equivalent to, and tends to be more rapid than, that in patients receiving histamine H2-receptor antagonists. In comparisons with omeprazole 20 mg/day, lansoprazole 30 mg/day produced duodenal ulcer healing more rapidly and reduced ulcer pain to a greater extent at 2 weeks, but overall healing rates were similar after 4 weeks of therapy.

At therapeutic dosages, lansoprazole produces superior healing and symptom relief of reflux oesophagitis in comparison with ranitidine, and it tends to relieve heartburn more effectively than omeprazole, although both agents produce equivalent healing. Healing of peptic ulcers or reflux oesophagitis refractory to histamine H2-receptor antagonists occurs after 8 weeks in the majority of patients treated with lansoprazole, and lansoprazole and omeprazole demonstrate similar efficacy in patients with refractory peptic ulcers. In patients with Zollinger-Elli-son syndrome, lansoprazole effectively controls mean basal gastric acid output.

Lansoprazole is generally well tolerated in clinical trials. The incidence of adverse effects is similar to that of omeprazole, ranitidine and famotidine in comparative studies.

Combination therapy with lansoprazole and antibacterial agents such as amoxicillin, tinidazole, roxithromycin and/or metronidazole appears to eradicate Helicobacter pylori in 22 to 80% of patients with this organism. Limited data also suggest that lansoprazole may have superior activity against H. pylori in comparison with omeprazole, although the clinical relevance of this preliminary finding requires further confirmation.

Thus, lansoprazole may be considered as an alternative to existing antisecretory agents available for the treatment of acid-related disorders, particularly because it may provide more rapid healing and relief of symptoms.

Pharmacodynamic Properties

Lansoprazole is metabolised to active sulphenamide derivatives in gastric parietal cells. These metabolites inactivate the sulfhydryl group of H+,K+-adenosine triphosphatase (ATPase), the enzyme catalysing the final step of the gastric acid secretion pathway, thus inhibiting both centrally and peripherally mediated gastric acid secretion. Increased mucosal oxygenation or bicarbonate secretion induced by lansoprazole may also protect the gastric mucosa from injury.

In healthy volunteers, single and multiple oral doses of lansoprazole inhibit both basal and stimulated gastric acid secretion, although the normal circadian rhythm of acid secretion is maintained. Inhibition of gastric acid secretion is dose-related over the range of 15 to 60mg and is approximately 80 to 97% after a single 30mg dose. 90% inhibition was noted after 7 days of therapy with lansoprazole 30 mg/day in 1 study. Inhibition of gastric acid secretion was also dose proportional in patients with a history of duodenal ulcer who received single or daily (for 7 days) doses of lansoprazole 10 to 30mg.

Unlike histamine H2-receptor antagonists, lansoprazole inhibits daytime and nocturnal acid secretion regardless of whether it is administered in the morning or the evening. Gastric acid inhibition is also similar when lansoprazole is administered before or after a meal. Lansoprazole has no effect on postprandial digestive function or gastric emptying. Lansoprazole inhibits pepsin secretion and activity in healthy volunteers, with greater inhibition observed when the drug is administered at night compared with in the morning.

In several studies conducted in patients with peptic ulcer, serum gastrin levels approximately doubled after 2 months of treatment with lansoprazole 30 to 60 mg/day, although levels returned to baseline within 1 to 12 weeks of discontinuing therapy. In a longer term study using the same dosages of lansoprazole, basal gastrin levels increased to 4 times normal values after 4 weeks, but no further increases were observed during the following 4 years of treatment. No significant change in enterochromaffin-like (ECL) cell density was observed in about 350 patients with acid-related disorders after 8 weeks of therapy with lansoprazole at dosages of up to 60 mg/day. However, ECL cell hyperplasia was seen in some patients with refractory peptic ulcers or reflux oesophagitis who received lansoprazole 30 to 120 mg/day for 30 months in 1 study, but no patient developed dysplastic lesions or carcinoids.

Eradication of Helicobacter pylori is associated with healing and maintenance of disease remission in patients with peptic ulcer. Lansoprazole has antimicrobial activity against H. pylori in vitro and is as effective as tripotassium dicitrato bismuthate (colloidal bismuth subcitrate) and 4 times more potent than omeprazole for eradication of this organism in vitro. H. pylori urease is also inhibited by lansoprazole in vitro.

Pharmacokinetic Properties

Lansoprazole is acid labile and is therefore administered as an enteric-coated formulation. Maximum serum lansoprazole concentrations (Cmax) of 0.75 to 1.15 mg/L are reached within 1.5 to 2.2 hours of oral administration of a 30mg dose to healthy volunteers. Cmax values are dose-proportional over the range 15 to 60mg. Although bioavailability shows marked interindividual variability, Cmax and bioavailability are not significantly altered by administration of multiple drug doses. Concomitant food intake delayed absorption, and reduced Cmax and bioavailability in some studies, but bioavailability was not altered in others. The bioavailability of lansoprazole was not affected by prior administration of antacid.

In the serum, lansoprazole is metabolised to 2 main excretory metabolites, lansoprazole sulphone and hydroxy-lansoprazole. Single and multiple doses of oral lansoprazole 15 to 60mg have a plasma elimination half-life of between 1.3 and 1.7 hours in healthy volunteers. Lansoprazole has not been recovered from the urine in an unchanged form. Conjugated and unconjugated hydroxylated metabolites of the drug are renally excreted, although they account for only 14 to 23% of the total administered dose of lansoprazole.

In healthy elderly volunteers, compared with younger volunteers, Cmax of lansoprazole was not significantly different, but area under the concentration-time curve values were increased and elimination was prolonged. Similarly, elimination was prolonged in patients with severe liver disease and in older patients (mean age 69 years) with mild renal impairment (creatinine clearance 2.4 to 3.6 L/h). In patients with more severe renal impairment (creatinine clearance less than 1.2 L/h), elimination was not significantly different from that of healthy volunteers.

Therapeutic Efficacy

Lansoprazole 30 mg/day provided effective symptom relief and healing of duodenal ulcer in 75 to 100% of patients after 4 weeks’ therapy in noncomparative and comparative trials. Similarly, in patients with gastric ulcer, the same dosage of lansoprazole produced healing rates of 50 to 79% after 4 weeks and 87 to 100% after 8 weeks.

Lansoprazole 30 mg/day produced superior healing rates in patients with duodenal and gastric ulcers compared with ranitidine 300 mg/day and was slightly more effective than famotidine 40 mg/day after 4 weeks of therapy in patients with duodenal ulcer. In patients with gastric ulcer, lansoprazole produced higher healing rates and faster healing than famotidine 20mg twice daily. Lansoprazole 30 mg/day healed duodenal ulcers more rapidly than therapeutic dosages of ranitidine or famotidine. Reductions in ulcer symptoms were at least equivalent in lansoprazole-treated patients with peptic ulcers and in patients who received histamine H2-receptor antagonists, but tended to be achieved more rapidly in lansoprazole recipients in some studies.

Lansoprazole 30 mg/day produced duodenal ulcer healing more rapidly than omeprazole 20 mg/day in 2 of 3 published studies (2-week healing rates of 74 to 88% vs 58 to 82%) and reduced ulcer pain to a greater extent after 2 weeks in 1 study, although healing rates were similar (at least 94%) after 4 weeks. In patients with gastric ulcer, lansoprazole produced superior healing rates to omeprazole after 8 weeks in an intent-to-treat analysis and relief of gastric pain tended to occur more rapidly with lansoprazole. However, healing rates were similar in both groups at 4 and 8 weeks in a per protocol analysis of the data.

Lansoprazole 30 mg/day produced endoscopically measured healing in 85 to 97% of patients with reflux oesophagitis after 8 weeks’ treatment and provided rapid relief of symptoms. Both healing and symptom relief were achieved more effectively with lansoprazole than with ranitidine 300 mg/day or placebo. Lansoprazole tended to relieve symptoms of oesophagitis more effectively than omeprazole 20 mg/day at 2 or 4 weeks, although both agents produced equivalent healing after 4 and 8 weeks. Patients with Barrett’s oesophagus were also effectively treated with lansoprazole 30 to 60 mg/day; in 1 study the beneficial effects of the drug were maintained for a mean of 2.7 years.

Preliminary results show that recurrence of duodenal ulcer or reflux oesophagitis was effectively prevented during 1 year of treatment with lansoprazole 15 or 30 mg/day, respectively, compared with placebo, in patients with healed lesions. Maintenance therapy with lansoprazole 15, 30 or 60 mg/day prevented or significantly reduced the incidence of recurrence for periods of up to 4 years in patients with healed lesions previously refractory to histamine H2-receptor antagonists.

Lansoprazole 30 or 60 mg/day generally produces healing of peptic ulcers or reflux oesophagitis refractory to histamine H2-receptor antagonists in 69 to 100% of patients after 8 weeks. Lansoprazole 30 mg/day and omeprazole 20 or 40 mg/day had similar efficacy in 2 studies conducted in patients with refractory peptic ulcers.

Although data concerning eradication rates with lansoprazole monotherapy are scarce, in clinical studies, lansoprazole 15 or 30 mg/day for 2 to 8 weeks appears to clear H. pylori from the gastric mucosa in 12 to 76% of patients with gastric or duodenal ulcers, and preliminary findings suggest that it may be more effective than omeprazole in this regard. Combination therapy with lansoprazole and antibacterial agents increased H. pylori eradication rates and healing of peptic ulcers compared with lansoprazole monotherapy. However, the incidence of ulcer recurrence after discontinuation of lansoprazole in patients in whom H. pylori infection has been eradicated requires further study.

In patients with Zollinger-Ellison syndrome, lansoprazole 15 to 180 mg/day controlled mean basal gastric acid output (less than 10 mmol/h), and preliminary evidence suggests that it is as effective as omeprazole 20 to 160 mg/day in patients with this disease.

Tolerability

Lansoprazole 15 to 60 mg/day is generally well tolerated in short term (up to 8 weeks) clinical trials. The incidence of adverse effects with placebo or therapeutic dosages of lansoprazole or comparator agents was similar. Tolerability data from 4749 volunteers or patients who received lansoprazole 7.5 to 120 mg/day (most commonly 30 mg/day) in clinical trials showed that the most frequent adverse events were gastrointestinal (9% of patients), particularly diarrhoea. Headache (4.7%), dizziness (1%), skin disorders (1.7%) and respiratory tract symptoms were also reported. The incidence of withdrawal from lansoprazole therapy was 1.2%. 1678 volunteers or patients received comparator drugs in these studies; the incidence of withdrawal from treatment was 1.1% with ranitidine, 0.1% with famotidine and 2.0% with omeprazole.

In clinical studies, laboratory abnormalities were uncommon in lansoprazole recipients, although serum gastrin levels increased in almost all studies, and increases in liver enzyme levels, haematocrit, haemoglobin levels, urinary protein excretion and uric acid levels were reported in a small number of patients. No clinically significant changes in steroid or thyroid hormone metabolism have been reported with lansoprazole therapy. Lansoprazole does not appear to significantly interact with other drugs metabolised by the cytochrome P450 enzyme system.

Studies assessing long term tolerability are scarce and will need to be conducted before the tolerability profile of lansoprazole can be fully elucidated.

Dosage and Administration

Although dosage recommendations vary from country to country, lansoprazole 15 or 30 mg/day for up to 4 weeks is generally administered for the short term treatment of patients with duodenal ulcer, while 30 mg/day for up to 8 weeks is recommended for treatment of patients with gastric ulcer or reflux oesophagitis. In patients with lesions refractory to histamine H2-receptor antagonist therapy, lansoprazole 30 to 60 mg/day for 8 to 12 weeks has been effective. Individualised dosages of 15 to 180 mg/day were effective at reducing gastric acid output to less than 10 mmol/h in patients with Zollinger-Ellison syndrome enrolled in clinical trials, and in some patients, dosage was reduced without loss of efficacy.

Lansoprazole is administered as encapsulated enteric-coated granules and is generally given in the morning before a meal.

Keywords

Peptic Ulcer Omeprazole Duodenal Ulcer Ranitidine Gastric Ulcer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Caroline M. Spencer
    • 1
  • Diana Faulds
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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