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Use of Lubiprostone in Constipating Disorders and Its Potential for Opioid-Induced Bowel Dysfunction

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Use of Lubiprostone in Constipating Disorders and Its Potential for Opioid-Induced Bowel Dysfunction DRUG EVALUATION Use of lubiprostone in constipating disorders and its potential for opioid-induced bowel dysfunction Lubiprostone is a novel medication, approved by the US FDA for the treatment of chronic idiopathic constipation in adults and constipation-predominant irritable bowel syndrome in adult women. It is an activator of the CIC-2 chloride channel, indirectly making more water available in the lumen of the gastrointestinal tract. Secondary stretching of the gastrointestinal wall possibly causes increased small- and large-bowel transit, making it beneficial in constipation-based conditions, not only chronic idiopathic constipation and constipation-predominant irritable bowel syndrome, but also possibly opioid-induced bowel dysfunction. Lubiprostone has some preclinical data to support its use in this indication, confirmed by the preliminary efficacy and safety results of the two, very recently completed, randomized, double-blind, placebo-controlled studies. KEYWORDS: chronic idiopathic constipation constipation-predominant Egilius LH Spierings irritable-bowel syndrome lubiprostone opioid-induced bowel dysfunction Department of Neurology, Brigham and Women’s Hospital, Harvard Medical Lubiprostone is a novel medication that, in in this case, of chloride ions, for which the School, and January 2006, was approved by the US FDA lipid-bilayer cell membrane is not permeable. It Craniofacial Pain Center, for the treatment of chronic idiopathic constipa- facilitates diffusion down a concentration gra- Department of General tion in adults, and in April 2008, was approved dient, which is created by the uptake of chloride Dentistry, Tufts University for the treatment of constipation-predominant ions into the cell across the basolateral mem- School of Dental Medicine irritable bowel syndrome (IBS) in adult women. brane through sodium–potassium–chloride 25 Walnut Street, This review will discuss lubiprostone’s pharma- cotransport activity. Suite 400, Wellesley Hills, cology, as well as its efficacy and safety in the In simplified terms, there are four types MA 02481-2150, USA approved indications; in addition the preclinical of chloride channels: voltage-gated, calcium- Tel.: +1 781 431 1113 and preliminary clinical efficacy and safety data gated, protein-kinase-gated and ligand-gated. Fax: +1 781 431 1086 supporting its potential usefulness in the treat- The CIC-2 channel, the selective target of [email protected] ment of opioid-induced bowel dysfunction will lubiprostone, is one of nine voltage-gated be presented. chloride channels. Activation of this channel results in an efflux of chloride ions from the Lubiprostone epithelial intracellular space into the lumen of Structure the gastro intestinal tract. The efflux of chloride ® Lubiprostone (SPI-211/RU-211, Amitiza ) [101] ions is followed by a flow of sodium ions from is a bicyclic fatty-acid derived from the 15-keto the gastro intestinal extracellular space through (FIGURE 1) metabolite of prostaglandin E1 . It is a paracellular pathways in between the epithelial member of a new class of compounds called pros- cells, to maintain electroneutrality. The accu- tones, a collective name for the 15-keto metabolites mulation of sodium ions in the gastrointestinal of natural prostaglandins and structurally similar lumen, in turn, draws extracellular water into compounds. The only other FDA-approved pros- the lumen to maintain osmotic balance. tone is unoprostone, indicated for the lowering of intraocular pressure in patients with open-angle Metabolism glaucoma or ocular hypertension. As a fatty acid, lubiprostone is highly lipophilic, but its absorption is negligible due to rapid Function metabolism locally in the gastrointestinal tract, Lubiprostone is an activator of the CIC-2 chlo- resulting in a bioavailability of less than 1%. Its ride channel, which is a transmembrane protein, main metabolite is M3 or 15-hydroxy-lubipros- located in the apical or luminal membrane of tone, which is pharmacologically active and does the epithelial cells lining the gastrointestinal get absorbed. However, its systemic bioavailabil- tract (FIGURE 2). The protein allows the passage, ity is also low, and accounts for less than 10% of 10.2217/THY.09.52 © 2009 Future Medicine Ltd Therapy (2009) 66(5),(5), 657–665 ISSN 1475-0708 657 DRUG EVALUATION Spierings Lubiprostone in opioid-induced bowel dysfunction DRUG EVALUATION also opioid-induced bowel dysfunction. The slow- O ing of gastric emptying, causing gastric disten- O H sion, may account for its most common adverse OH event, nausea. H An important function of the colon is to extract water from the stool; with the increased transit H the colon has less time to perform this function, O resulting in softer stool, which, in turn, is easier to evacuate. A schematic of lubi prostone’s mode of HO action in relieving constipation-based conditions F is shown in FIGURE 3. F CH3 From a safety perspective, the studies in healthy volunteers have shown lubiprostone not to affect Figure 1. Lubiprostone. serum electrolytes and not to impact the elec- trocardiogram, which was also confirmed in the the administered lubiprostone dose. It has a time studies of lubiprostone in subjects with chronic to maximum plasma concentration and plasma- constipation and constipation-predominant IBS elimination half-life of approximately 1 h; its reviewed below. protein binding is 94%. Chronic idiopathic constipation Mode of action Definition In healthy volunteers, lubiprostone has been Rome III refers to chronic idiopathic constipa- shown to decrease gastric emptying and increase tion as functional constipation that presents as small-bowel and large-bowel transit [1], but not to persistently difficult, infrequent or seemingly increase colonic motor function [2]. The motility incomplete defecation, not meeting IBS crite- effects that occur with lubiprostone are secondary ria [3]. It estimates constipation to occur in up to the secretion of water it causes into the lumen of to 27% of the population, affecting all ages, and the gastrointestinal tract. The increased water, in to be most common in women and nonwhites. turn, distends the gastro intestinal tract and causes The diagnostic criteria listed for functional mural stretching, delaying gastric emptying to constipation require them to be fulfilled for facilitate digestion and accelerating bowel transit the last 3 months, with symptom onset at least to facilitate stool evacuation. The latter makes the 6 months prior to diagnosis: medication beneficial in constipation-based con- Must include two or more of the following: ditions, such as chronic idiopathic constipation, constipation-predominant IBS and, potentially, – Straining during at least 25% of defecations – Hard or lumpy stools in at least 25% of Apical Basolateral defecations – Sensation of incomplete evacuation for at least 25% of defecations CFTR - Cl + Cl- channel K Cl- Na–K–2Cl – Sensation of anorectal obstruction or Na+ cotransporter blockage for at least 25% of defecations Na+ ClC-2 - + Cl ~ Na pump – Manual maneuvers to facilitate in at least Cl- channel K+ 25% of defecations + K+ channel K – Fewer than three defecations per week Loose (mushy) or watery stools are rarely Na+ Paracellular path present without the use of laxatives There are insufficient criteria for IBS Figure 2. Chloride-ion (Cl-) transport in intestinal epithelial cells. At the basolateral membrane, chloride ions enter the cell from the blood across the In the above diagnostic criteria, hard or sodium–potassium–chloride (Na–K–2Cl) cotransporter. Sodium ions are expelled lumpy stools is defined as types 1 or 2 of the by the sodium pump and potassium ions leave via a potassium channel. Sodium Bristol Stool Form Scale – that is, separate ions are shown crossing the cell layer via a paracellular pathway, but sodium hard lumps like nuts (difficult to pass) or sau- channels also exist (not shown). Reproduced with permission from [11]. sage shaped but lumpy; loose (mushy) or watery 658 Therapy (2009) 6(5) future science group DRUG EVALUATION Spierings Lubiprostone in opioid-induced bowel dysfunction DRUG EVALUATION Lubiprostone Increased intraluminal chloride Increased intraluminal sodium Decreased Increased Softer stool water intraluminal absorption water Decreased Increased transit time intraluminal Easier volume evacuation Increased Luminal Easier motility distension evacuation Mural stretching Figure 3. Mode of action of lubiprostone in constipation-based conditions. stools are defined as types 6 or 7 on the Bristol 33 subjects were randomized to placebo, Stool Form Scale – that is, fluffy pieces with 30 subjects to 24-µg lubiprostone, 32 subjects ragged edges, a mushy or watery stool, no solid to 48-µg lubiprostone and 34 subjects to 72-µg pieces or entirely liquid. lubiprostone. A spontaneous bowel movement was defined as a bowel movement not preceded Lubiprostone within 24 h by intake of rescue medication, Dose exploration consisting of a 10-mg bisacodyl suppository or A randomized, double-blind, placebo-controlled a sodium-phosphate enema. The subjects also study evaluated lubiprostone in the treatment had to have abdominal bloating or discomfort of chronic idiopathic constipation in doses and one or more of the following symptoms: of 24, 48 and 72 µg per day, administered as (very) hard stool, subjectively incomplete evacu- 24 µg once-daily, twice-daily and three-times ation and straining at defecation. The eligibil- daily, respectively, for 3 weeks [4]. The study ity requirements
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