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September 2007 ® Volume 22, Issue 12 September 2007 review lubiprostone’s kinetics, safety, and efficacy data. LUBIPROSTONE (AMITIZA®): Pharmacology and Pharmacokinetics THE FIRST CHLORIDE CHANNEL Lubiprostone, also referred to as SPI-0211 or ACTIVATOR FOR THE TREAT- RU-0211, is the first of a new class of drugs called MENT OF CHRONIC IDIOPATHIC prostones. These prostones are bicyclic fatty acids CONSTIPATION that are derivatives of a metabolite of prostaglandin E1, though they have a negligible effect on pros- 5 Stacie Williams, Pharm.D. Candidate taglandins E and F. Type 2 chloride channels are located on the apical portion of gastrointestinal (GI) epithelium. Once they are activated, chloride moves out of these cells into the lumen of the intestinal Constipation is an exceedingly common com- tract. Sodium follows chloride out of the cell in order plaint. Recent reports estimate that between 2% and to retain neutrality. Once sodium leaves, water does 27% of North Americans suffer from constipation.1 as well so that isotonicity is maintained.6 This leads For many patients, constipation is a chronic condi- to an increase in intestinal fluid so that stools are sof- tion that lasts for months and can potentially become tened and motility increased. Serum electrolyte con- severe. In 2002, 398,000 people were hospitalized centrations remain unaltered.7 Lubiprostone is highly for constipation and of these 121 deaths occurred.2 specific for ClC-2 channels; CFTR is not activated There are many prescription and non-prescription by this compound.8 products that have been marketed for constipation. Lubiprostone is administered orally, but due These include the bulk-forming, osmotic, stimulant, to low systemic availability, plasma concentrations and lubricant laxatives and stool softeners. Some pa- are so low they cannot be quantified. Metabolism tients can achieve full relief from these products, al- occurs by oxidation and reduction via carbonyl re- though some remain symptomatic. The discovery of a new type of chloride channel may be the answer for those patients who have chronic constipation. Most of the chloride transport INSIDE THIS ISSUE: in the intestinal epithelium is through the cystic fi- ® brosis transmembrane conductance regulator LUBIPROSTONE (AMITIZA ): THE FIRST CHLORIDE (CFTR), but it was found that there are also type 2 CHANNEL ACTIVATOR FOR THE TREATMENT OF chloride channels (ClC-2) in these cells.3 Lubipros- CHRONIC IDIOPATHIC CONSTIPATION tone (Amitiza® [ă mə tē′ zə]) is a new drug that acti- ® vates ClC-2 channels in order to alleviate constipa- ALLI : AN OVER-THE-COUNTER ORLISTAT tion. The manufacturer, Takeda Pharmaceuticals, received approval by the FDA in January 2006 to market lubiprostone for the indication of chronic idiopathic constipation in adults.4 This article will 1 PharmaNote Volume 22, Issue 12 September 2007 ductase.7 The hepatic CYP450 system is not respon- chronic constipation.9 In this study, chronic constipa- sible for its metabolism, so there is a low likelihood tion was defined as < 3 spontaneous bowel move- of drug-drug interactions. Lubiprostone does not in- ments (SBM) per week plus at least 6 months with 1 hibit cytochrome P450 isoforms 3A4, 2D6, 1A2, or more symptoms from Rome II criteria (Table 1). 2A6, 2B6, 2C9, 2C19, or 2E1, and in-vitro studies of Among the participants, 90% were females, 86% human hepatocytes show no induction of the cyto- were white, and the average age was 48.6 years. chrome P450 isoforms 1A2, 2B6, 2C9, and 3A4. There was a 2-week washout period before patients There is one active metabolite, M3, which has a Cmax were randomized to lubiprostone 24 mcg BID or pla- of 41.9 pg/mL and reaches peak plasma concentra- cebo for 4 weeks. The patients were then followed tion after 1.14 hours. After a single oral dose of 72 for 2 weeks with no drug to assess outcomes. Pa- mcg radiolabeled lubiprostone, 60% of the total dose tients kept a diary to record bowel movements as was recovered in the urine within 24 hours and 30% well as symptoms experienced during the trial. There of the was recovered in the feces by 168 hours. Food was a significant increase in the number of mean does not alter the kinetics of this drug, but it is rec- weekly SBM in the lubiprostone group: 5.1 to 5.7 ommended that it be taken with food to minimize compared to 2.8 to 3.5 in the placebo group (p < nausea. Lubiprostone has not yet been studied in pa- 0.002). A significant increase in the number of bowel tients with hepatic or renal impairment.4 movements on day one was also observed with 57% in the lubiprostone group and 37% in the placebo Clinical Trials group (p < 0.003). Other improvements associated There have been a few studies published that with lubiprostone included reduced straining and im- look at the safety and efficacy of lubiprostone for proved stool consistency. treating constipation. One preclinical study focused A second Phase III study was a double- on determining its effect on gastric/intestinal func- blinded, multicenter, randomized, placebo-controlled tion and transit.5 This was a randomized, double- trial of 237 patients (88% of which were females).11 blind, placebo-controlled study whose endpoints This consisted of a 15-day washout period then 28 were meal volumes tolerated, postprandial symp- days of lubiprostone 24 mcg BID or placebo. The toms, as well as gastric volumes in 30 healthy sub- primary endpoint of this study was SBM frequency. jects. At 24 mcg twice a day (BID), lubiprostone The mean weekly SBM before treatment was 1.28 in increased small bowel and colonic transit, but de- the lubiprostone group vs. 1.52 in the placebo group. layed gastric emptying. Fasting gastric volume was After 28 days of treatment, the number of weekly also increased. There was no significant effect on SBM increased with a significant difference between postprandial gastric volume or symptoms associated groups (5.89 for lubiprostone vs. 3.99 for placebo; p with meals. < 0.001). There was a significant amount of patients There were two Phase III clinical trials con- that were classified as complete responders (defined ducted using lubiprostone for chronic constipation. as >4 SBM per week without using rescue drugs) in The first of the two was a randomized, double-blind, the lubiprostone group after week one compared to placebo-controlled trial using 242 patients with those who received placebo (72.1% vs. 48.7%; p < 0.001). In 61.3% of patients receiving lubiprostone, 10 Table 1. Symptoms described in Rome II criteria there was a SBM within 24 hours of the first dose, Straining in >25% of defecations compared to 31.4% in the placebo group. Table 2 summarizes the results of Phase III trials. Lumpy or hard stools in >25% of defecations Sensation of incomplete evacuation in >25% of defecations Dosing and Administration Lubiprostone is currently available in 24 mcg Sensation of anorectal obstruction/blockade in >25% of defe- gelatin capsules to be given orally. It is dosed at 24 cations mcg BID in adults and elderly and can be reduced to once daily if nausea is persistent. The recommended Manual maneuvers (digital evacuation, support of pelvic floor) maximum dose is 48 mcg/day. It has not been stud- to help progress defecation >25% of the time ied in children and should not be recommended in this population. Lubiprostone can be taken with or Fewer than 3 defecations/week 2 PharmaNote Volume 22, Issue 12 September 2007 Table 2. Comparison of lubiprostone phase III trials Study group Design Dose Average SBM per week* SBM within first 24 hrs* Placebo 3.1 37% Johanson et al.9 Randomized, DB, PC 2003 N = 242 Lubiprostone 24 mcg BID 5.3 57% (p < 0.002) (p < 0.003) Placebo 3.99 31.4% Randomized, DB, Johanson et al.11 PC, multicenter 2005 Lubiprostone 24 mcg BID 5.89 61.3% N = 237 (p <0.001) (no p value) SBM = spontaneous bowel movement, DB = double-blinded, PC = placebo-controlled, N = number of patients * Comparisons to placebo without food, although nausea may be reduced if it is the most prevalent adverse effect, occurring in 31.1% taken with meals.7 No limitations have been placed of those treated with lubiprostone compared to 5.1% on the length of using lubiprostone. in the placebo group. With all of the clinical trials combined, over 1100 patients received 24 mcg BID Toxicity and Safety of lupiprostone; 3.4% reported severe nausea and Lubiprostone is safe and tolerated fairly well 8.7% stopped treatment due to nausea. The lowest by patients in clinical trials. The most common ad- overall incidence for nausea was seen at 24 mcg/day verse effects are gastrointestinal events. Nausea was (17.2%) and the incidence of nausea increased with Table 3. Percentage of adverse events in greater than 1% of patients in clinical trials4 Lubiprostone Placebo 24 mcg BID Adverse Event (N=316) (N=1113) % % Nausea 31.1 5.1 Vomiting 4.6 0.9 Headache 13.2 6.6 Diarrhea 13.2 0.9 Abdominal distention 7.1 2.2 Abdominal pain 6.7 2.8 Flatulence 6.1 1.9 Dizziness 4.1 1.3 Peripheral edema 3.8 0.3 Arthralgia 3.1 0.3 Dyspepsia 2.9 1.3 Chest pain 1.1 0.0 Dyspnea 2.4 0.0 Fatigue 2.3 1.9 3 PharmaNote Volume 22, Issue 12 September 2007 higher doses. The incidence of nausea was improved References when lubiprostone was taken with food; therefore, it 1. Harris LA. Prevalence and ramifications of is recommended that it be taken with a meal. Diar- chronic constipation.
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