Lansoprazole

Summary

Synopsis

Lansoprazole is an effective acid pump inhibitor acting at the final enzymatic step of the acid secretory pathway of the parietal cell, decreasing gastric acid secretion regardless of the primary stimulus.

Results of short term (<8 weeks) clinical trials have shown lansoprazole to be significantly superior to placebo and ranitidine in the treatment of duodenal ulcer, both in the rate of healing and in overall healing at 4 weeks. Lansoprazole appears to heal duodenal ulcer more quickly than famotidine, and demonstrates slightly greater efficacy at 4 weeks, although both drugs appear to have equivalent efficacy overall. Gastric ulcers and reflux oesophagitis are also healed by lansoprazole 30 mg/day for 4 to 8 weeks, with healing rates after 8 weeks of approximately 85 to 95% for both indications. Lansoprazole appears to be superior to ranitidine and comparable to omeprazole in treating reflux oesophagitis. Furthermore, lansoprazole has relieved reflux symptoms more quickly than either ranitidine or omeprazole. Preliminary data also indicate that lansoprazole may be effective in the treatment of peptic ulcer disease and reflux oesophagitis refractory to H₂-receptor antagonists, and in patients with Zollinger-Ellison syndrome. While direct comparisons with omeprazole are limited, results suggest that lansoprazole, used for short term treatment, is at least as effective as omeprazole in the treatment of peptic ulcer and reflux oesphagitis.

Lansoprazole has been well tolerated in short term clinical trials, with an incidence of adverse effects comparable with that of other agents in its therapeutic class. Trials assessing long term tolerability data are ongoing and will be required as part of the assessment of the safety profile, if lansoprazole is to be used prophylactically to prevent ulcer recurrence.

Thus, by virtue of its ability to heal ulcers and rapidly relieve associated symptomatology, lansoprazole represents a useful alternative for the treatment of acid related disorders.

Pharmacodynamic Properties

Lansoprazole, a substituted benzimidazole derivative, is converted in the acidic environment of the canaliculi of the gastric parietal cell to active sulphenamide derivatives which bind to the sulphydryl group of H⁺,K⁺-ATPase, the enzyme catalysing the final step in the acid secretion pathway, thereby inactivating H⁺,K⁺-ATPase and producing inhibition of both centrally and peripherally mediated gastric acid secretion.

In in vitro studies lansoprazole appears to be at least as potent as omeprazole at inhibiting gastric acid secretion. In some in vivo animal models lansoprazole is less potent than the H₂-receptor antagonists ranitidine and famotidine and as effective as omeprazole. In animal models lansoprazole inhibited gastric acid secretion to a greater extent when administered intravenously rather than orally and was effective regardless of the primary stimulus.

In humans, orally administered lansoprazole causes dose-proportional inhibition of acid secretion over the range of 15 to 60mg. Inhibition is approximately 80% after an initial 30mg dose and 90% after 7 days therapy with a once daily 30mg dose. Unlike H²-receptor antagonists, lansoprazole inhibits daytime and nocturnal acid secretion regardless of whether it is administered in the morning or the evening. Lansoprazole also decreases the volume of gastric acid secretion and inhibits the secretion and activity of pepsin.

Short term clinical studies indicate that lansoprazole 30 mg/day for 2 months causes an approximate doubling in serum gastrin levels in patients with peptic ulcer, but these return to baseline within several days to 4 weeks of discontinuing therapy. A longer term study of 12 months duration has demonstrated that lansoprazole 60mg daily also significantly increases serum gastrin levels. Increased serum gastrin levels occur as a result of gastric acid suppression, whether achieved pharmacologically or surgically, and as yet do not appear to be associated with any significant changes in gastric mucosal morphology in humans. In rats, life-long administration of other acid-suppressing drugs at high doses has resulted in the development of enterochromaffinlike cell carcinoids; however, this has not been reported with lansoprazole to date. The effect of lansoprazole on the gastric mucosa of humans, over periods of greater than 2 months, has not yet been reported.

Lansoprazole appears to prevent experimentally induced ulcers in animals, and in humans a 30 or 60mg daily dose appears to protect against aspirin-induced mucosal injury.

In vitro and preliminary clinical data indicate that lansoprazole may clear Helicobacter pylori, an organism which has been associated with relapse of peptic ulcer, from the gastric mucosa. However, these preliminary findings need confirmation, in particular, whether initial eradication of H. pylori persists after treatment with lansoprazole is completed.

Pharmacokinetic Properties

Because of its instability in acidic conditions, lansoprazole is administered as an enteric-coated formulation. Maximum serum lansoprazole concentrations of 1038 μg/L have been reached within approximately 2 hours of administration of a 30mg encapsulated enteric-coated dose. Concomitant food intake delays absorption and has reduced bioavailability in some studies. Bioavailability varies between individuals but appears to be dose-proportional. Most studies have reported no significant increase in bioavailability after repeated administration of lansoprazole over a 7-day period.

While lansoprazole is converted to the active compounds AG-1812 and AG-2000 in the acidic environment of the parietal cell, in the serum lansoprazole is rapidly and completely metabolised to 2 main excretory metabolites, lansoprazole sulphone and hydroxylansoprazole. Approximately 14 to 23% of a dose is excreted in the urine as conjugated and unconjugated hydroxylated metabolites but unchanged lansoprazole has not been detected in the urine. The mean elimination half-life of lansoprazole is between 1.3 and 1.7 hours in healthy volunteers after a single dose, is about 2 hours in the elderly and in patients with severe hepatic dysfunction is prolonged to 7 hours. Serum lansoprazole concentrations do not correlate with antisecretory activity and indeed, antisecretory activity is apparent for many hours after the drug is undetectable in the serum.

Therapeutic Efficacy

Lansoprazole 30 mg/day heals duodenal ulcers after 2 to 4 weeks, with healing rates of 75 to 100% after 4 weeks. Most studies have found that lansoprazole 30mg once daily provides increased healing rates and more rapid healing than ranitidine: healing rates at 2 weeks were about 75 to 80% with lansoprazole and 45 to 60% with ranitidine, and about 93 to 95% and 80%, respectively, after 4 weeks. A typical study shows that lansoprazole heals more rapidly than famotidine (healing rate at 2 weeks of 52 vs 37%) and is slightly more effective after 4 weeks (healing rates of 89 vs 80%). Lansoprazole also appears to heal more rapidly than orneprazole (healing rate at 2 weeks of 74 vs 58%), but both drugs were equally effective after 4 weeks. Ulcer-related pain is reduced rapidly by lansoprazole 30 and 60 mg/day; in one study lansoprazole 30 mg/day relieved pain more quickly than ranitidine 300 mg/day, producing complete pain relief after a median of 3 days vs 7 for ranitidine. A 60mg daily dose may be superior to ranitidine in relieving epigastric pain; relative effects with lower doses have been equivocal. Some investigators have reported that lansoprazole 30mg daily has a tendency to relieve more patients of ulcer symptomatology than famotidine 40 mg/day after 1 week of treatment, but others report that both drugs were similarly effective.

Patients with gastric ulcer require longer term treatment and are generally treated with lansoprazole 30 mg/day for 4 to 8 weeks. Healing rates achieved with lansoprazole 30mg daily after 4 and 8 weeks were 50 to 79% and 87 to 99%, respectively. Lansoprazole 30 mg/day healed gastric ulcer more effectively than ranitidine 300 mg/day at 4 weeks (healing rates of 73 to 78% vs 56 to 61%) and after 8 weeks provided slightly greater healing (99 vs 91%). Lansoprazole 30mg daily was more effective at healing gastric ulcer than famotidine 20mg twice daily after 2, 4 and 8 weeks and reduced symptoms more rapidly, but both drugs provided similar symptomatic relief after 8 weeks. Lansoprazole 30 mg/day was more effective than omeprazole 20mg daily in healing gastric ulcer after 8 weeks (healing rates of 93 vs 82%).

The efficacy of lansoprazole as maintenance therapy for preventing relapse of peptic ulcer has not yet been reported, although studies are in progress. Given the high relapse rate of peptic ulcer when any acid-suppressing therapy, including lansoprazole, is withdrawn, clinical trials to investigate the potential of lansoprazole in this indication are warranted.

Reflux oesophagitis is effectively treated with lansoprazole 30 mg/day with healing rates of 63 to 84% after 4 weeks and 85% to 92% after 8 weeks. Lansoprazole appears to be superior to ranitidine and equivalent to omeprazole in healing patients with this indication. Lansoprazole has relieved symptoms of heartburn significantly better than ranitidine and omeprazole after 4 weeks of treatment.

Preliminary data indicate that lansoprazole is effective in patients with peptic ulcers or reflux oesophagitis refractory to H₂-receptor antagonists: at doses of 30 mg/day administered for 8 weeks healing rates of 69 to 100% were achieved. Further healing may result if the dose is increased to 60 mg/day from week 8. Lansoprazole 60 to 120 mg/day (administered once or twice daily) reduced mean gastric acid output in patients with Zollinger-Ellison syndrome to <10 mmol/h in the hour preceding the next dose, and there is some preliminary indirect evidence that lansoprazole may be as effective as omeprazole in controlling acid secretion in patients with this disease.

Tolerability

Lansoprazole is well tolerated by patients in short term (< 8 weeks) clinical trials but there are no published reports of its longer term tolerability. Diarrhoea, headache, nausea and dermatological reactions are the most frequently reported adverse effects, occurring in < 2% of patients, but these are usually mild and transient. Occasional abnormalities in liver function tests and in complete blood counts have also been reported but these have generally been clinically insignificant. Only 9 patients (from a total of about 2100 patients) in clinical studies have discontinued therapy as a result of adverse effects. The incidence of adverse effects due to lansoprazole was not different from that reported in placebo recipients, and in comparative studies was generally similar to the incidence observed in patients treated with histamine H₂-receptor antagonists or omeprazole.

Dosage and Administration

A daily dose of lansoprazole 30mg, administered in the morning or the evening, is recommended for the treatment of duodenal ulcer and reflux oesophagitis. Similar regimens have been administered to patients with gastric ulcer or refractory disease. Lansoprazole therapy is usually required for 2 to 4 weeks for the treatment of duodenal ulcer and for 4 to 8 weeks for the treatment of gastic ulcer or reflux oesophagitis. Doses of 60 mg/day have been administered if ulcers are not healed after 6 to 8 weeks. In patients with Zollinger-Ellison syndrome the dose should be individualised to reduce and maintain the basal acid output between 0 and 10 mmol/h, and doses of up to 120 mg/day have been given for this indication.