Plecanatide

Plecanatide is a structural analog of human uroguanylin, and similarly to uroguanylin, plecanatide functions as a guanylate cyclase-C (GC-C) agonist. Both plecanatide and its active metabolite bind to GC-C and act locally on the luminal surface of the intestinal epithelium. Activation of GC-C results in an increase in both intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP). Elevation of extracellular cGMP has been associated with a decrease in the activity of pain-sensing nerves in animal models of visceral pain. Elevation of intracellular cGMP stimulates secretion of chloride and bicarbonate into the intestinal lumen, mainly through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, resulting in increased intestinal fluid and accelerated transit. In animal models, plecanatide has been shown to increase fluid secretion into the gastrointestinal (GI) tract, accelerate intestinal transit, and cause changes in stool consistency.

In an animal model of visceral pain, plecanatide reduced abdominal muscle contractions, a measure of intestinal pain.

Food Effect

Subjects who received either a low-fat, low calorie (LF-LC) meal or a high fat, high calorie (HF-HC) meal reported looser stools than fasted subjects up to 24 hours after a single dose of plecanatide 9 mg (3 times the recommended dose). In clinical studies, plecanatide was administered with or without food.

Absorption

Plecanatide was minimally absorbed with negligible systemic availability following oral administration. Concentrations of plecanatide and its active metabolite in plasma were below the limit of quantitation in the majority of analyzed plasma samples after multiple oral dosing of plecanatide 3 mg once daily up to 12 weeks. Therefore, standard pharmacokinetic parameters such as AUC, maximum concentration (C_max), and half-life (t_½) could not be calculated.

Food Effect

In a crossover study, 24 healthy subjects were given a single dose of plecanatide 9 mg (3 times the recommended dose) in 3 different states: fasted; following a low-fat, low-calorie meal (LF-LC; approximately 350 calories: 17% from fat, 66% from carbohydrate, and 17% from protein); and following a high-fat, high-calorie meal (HF-HC; approximately 1000 calories: 60% from fat, 25% from carbohydrate, and 15% from protein). Plecanatide was detected in 1 subject (fasted state) at 0.5 and 1 hour post-dose. Plecanatide concentrations were below the limit of quantitation for all other time points and for all other subjects. The active metabolite was not detected in any subject.

Distribution

Given that plecanatide concentrations following clinically relevant oral doses were not measurable, plecanatide is expected to be minimally distributed in tissues. Oral plecanatide was localized to the GI tract where it exerted its effects as a GC-C agonist with negligible systemic exposure. Plecanatide exhibited little to no binding to human serum albumin or human α-1-acid glycoprotein.

Elimination

Metabolism

Plecanatide was metabolized in the GI tract to an active metabolite by loss of the terminal leucine moiety. Both plecanatide and the metabolite were proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.

Excretion

No excretion studies have been conducted in humans. Plecanatide and its active metabolite were not measurable in plasma following administration of the recommended clinical doses.

Drug Interaction Studies

Neither plecanatide nor its active metabolite inhibited the cytochrome P450 (CYP) enzymes 2C9 and 3A4, and they did not induce CYP3A4 in vitro.

Plecanatide and its active metabolite were neither substrates nor inhibitors of the transporters P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in vitro.