On January 31, 2006, the US Food and Drug Administration (FDA) announced their official approval of lubiprostone (Amitiza, Sucampo/Takeda) for the treatment of chronic idiopathic constipation in both men and women over the age of 18. Lubiprostone is an oral medication, administered twice daily, in the form of a soft gelatin capsule containing 24 µg of active agent.
Lubiprostone is a first-in-class prostone, with the chemical structure of a bicyclic fatty acid. It promotes secretion of chloride into the gut through binding with the apical cell membrane and subsequent stimulation of specific calcium channels, labeled ClC-2 channels. Secretion of chloride anions into the gut lumen leads to the secretion of sodium, which is then followed by water. The resulting localized bolus of water and electrolytes (water) likely stimulates localized mechanoreceptors, thereby initiating a peristaltic wave and promoting spontaneous bowel movements (SBM). Lubiprostone acts locally in the gut and is minimally absorbed. A phase II dose-ranging study of lubiprostone examined doses as high as 72 µg daily and the higher doses did not perform significantly better in terms of efficacy.
Results of two nearly identical phase III trials led to FDA approval of lubiprostone. Each was a well-designed, randomized, double-blinded, placebo-controlled 4-week study. Both studies included a run-in period of 2 weeks of symptom monitoring. This was followed by a 4-week study period where patients were randomized to either placebo or 24 µg of lubiprostone twice daily. Afterward, the medication was stopped and patients were monitored for an additional 2 weeks. Patients were required to have had symptoms of chronic constipation (fewer than three bowel movements per week) continuously for at least 6 months prior to study entry. They were also required to experience at least one other symptom (25% of the time) such as straining, incomplete evacuation, or hard stools.
The combined patient population for both trials was 479. The primary efficacy outcome was an increase in weekly SBMs. In patients aged 18–65, the pooled rate of response to lubiprostone was estimated at 81% at the end of week 1 and 69% at week 4. In the placebo group, response was measured at 61% and 49%, at weeks 1 and 4, respectively. Initial average weekly bowel movements in both groups were measured at 1.5. This average was increased and sustained throughout the study to 5.3 in the treatment group and 2.9 in the placebo group. A separate analysis of patients aged 65 or older revealed a similar therapeutic gain of approximately 20% for spontaneous bowel movements.
There were no serious adverse events in the lubiprostone-treated patients. The most common reported side effect was nausea, which occurred in 31% of the lubiprostone-treated patients versus 5% of those taking placebo. Of the patients experiencing nausea, 6.6% discontinued therapy. Observational data suggest that taking lubiprostone with meals lessens symptoms of nausea.
Lubiprostone represents a new approach to the treatment of chronic constipation and is an alternative for patients who are resistant to or intolerant of currently available prescription medications, including Miralax/Glycolax formulations, lactulose, and tegaserod maleate (Zelnorm, Novartis). Currently, there are no direct head-to-head trials comparing these three drug classes for the treatment of chronic constipation and additional research is needed to determine which patients are best suited to which treatment. Until then, it should be noted that lubiprostone has been proven safe and efficacious in these initial placebo-controlled trials and presents a viable, wholly new alternative to existing therapies.