Constipation is the difficult or infrequent passage of stool, often accompanied by straining or a sensation of incomplete evacuation. Chronic idiopathic constipation (CIC) is a functional gastro intestinal (GI) disorder with features like those of constipation that occur for at least three months, but there is usually no evident underlying physiological abnormality.1,2 Although a number of definitions of CIC have been proposed, the Rome criteria are most often used in clinical trials and, therefore, most relevant when evaluating medications to manage this condition. The Rome criteria look at the frequency of straining, lumpy or hard stools, and sensation of incomplete evacuation, among other symptoms. The prevalence of CIC in North America is approximately 14%.3 Traditional treatment options for chronic constipation include lifestyle modifications, such as increased fluid intake and increased exercise.4 Fluid works to increase stool volume by augmenting luminal fluid, and increasing exercise improves motility by decreasing GI transit time.5 Fiber therapy is considered an effective option for the management of CIC, although the side effects can limit use. Osmotic laxatives and some stimulant laxatives have been studied and can also provide benefit.1,2.Plecanatide powder
Prior to 2017, there were only two medications approved for adults
with CIC: linaclotide (Linzess, Allergan) and lubiprostone (Amitiza,
Sucampo AG). Linaclotide is a guanylate cyclase-C (GC-C) agonist, and
lubiprostone is a chloride-channel activator.6 Both pro-secratory agents
have been shown to be effective and well tolerated for the treatment of
adults with CIC. Linaclotide is also approved for the treatment of
irritable bowel syndrome with constipation (IBS-C), and lubiprostone is
approved for the treatment of IBS-C only in women as well as
opioid-induced constipation in certain patients. These agents have not
been studied head to head, and both drugs were compared with placebo
when studied versus standard of care. In January 2017, the Food and Drug
Administration approved another GC-C agonist—plecanatide (Trulance,
Synergy Pharmaceuticals)—for the treatment of CIC in adults, and in
January 2018, the agency approved an additional plecanatide indication
for the treatment of IBS-C.7,8
Plecanatide, a GC-C agonist, is a
16-amino-acid peptide with the chemical name: L-Leucine,
L-asparaginyl-L--α-aspartyl-L-α=-glutamyl-L-cysteinyl-L-α-glutamyl-L-leucyl-L-cysteinyl-Lvalyl-L-asparaginyl-L-valyl-L-alanyl-Lcysteinyl-L-threonylglycyl-Lcysteinyl-,
cyclic (4→12),(7→15)-bis(disulfide). The molecular formula of
plecanatide is C65H104N18O26S4, and the molecular weight is 1682
daltons. The amino acid sequence for plecanatide is shown in Figure 1.
The solid lines linking cysteines illustrate disulfide bridges.
Plecanatide is an amorphous white to off-white powder that is soluble in
water. It is supplied as a 3-mg tablet for oral administration. The
inactive ingredients consist of magnesium stearate and microcrystalline
cellulose.8
