Linaclotide

Linaclotide is a Guanylate Cyclase-C receptor agonist (GCCA) with visceral analgesic and secretory activities.

Linaclotide is a 14-amino acid synthetic peptide structurally related to the endogenous guanylin peptide family. Both linaclotide and its active metabolite bind to the GC-C receptor, on the luminal surface of the intestinal epithelium. Through its action at GC-C, linaclotide has been shown to reduce visceral pain and increase GI transit in animal models and increase colonic transit in humans. Activation of GC-C results in an increase in concentrations of cyclic guanosine monophosphate (cGMP), both extracellularly and intracellularly. Extracellular cGMP decreases pain-fiber activity, resulting in reduced visceral pain in animal models. Intracellular cGMP causes secretion of chloride and bicarbonate into the intestinal lumen, through activation of the cystic fibrosis transmembrane conductance regulator (CFTR), which results in increased intestinal fluid and accelerated transit.

Pharmacodynamic effects

In a cross-over food interaction study, 18 healthy subjects were administered linaclotide 290 micrograms for 7 days both in the fasting and fed state. Taking linaclotide immediately after a high fat breakfast resulted in more frequent and looser stools, as well as more gastrointestinal adverse events, compared with taking it in the fasted state.

Absorption

In general, linaclotide is minimally detectable in plasma following therapeutic oral doses and therefore standard pharmacokinetic parameters cannot be calculated.

Following single doses of up to 966 micrograms and multiple doses up to 290 micrograms of linaclotide, there were no detectable plasma levels of parent compound or the active metabolite (des-tyrosine). When 2,897 micrograms was administered on day 8, following a 7-day course of 290 micrograms/day, linaclotide was detectable in only 2 of 18 subjects at concentrations just above the lower limit of quantification of 0.2 ng/ml (concentrations ranged from 0.212 to 0.735 ng/ml). In the two pivotal phase 3 studies in which patients were dosed with 290 micrograms of linaclotide once daily, linaclotide was only detected in 2 out of 162 patients approximately 2 h following the initial linaclotide dose (concentrations were 0.241 ng/ml to 0.239 ng/ml) and in none of the 162 patients after 4 weeks of treatment. The active metabolite was not detected in any of the 162 patients at any time point.

Distribution

As linaclotide is rarely detectable in plasma following therapeutic doses, standard distribution studies have not been conducted. It is expected that linaclotide is negligibly or not systemically distributed.

Biotransformation

Linaclotide is metabolised locally within the gastrointestinal tract to its active primary metabolite, des- tyrosine. Both linaclotide and des-tyrosine active metabolite are reduced and enzymatically proteolyzed within the gastrointestinal tract to smaller peptides and naturally occurring amino acids. The potential inhibitory activity of linaclotide and its active primary metabolite MM-419447 on the human efflux transporters BCRP, MRP2, MRP3, and MRP4 and the human uptake transporters OATP1B1, OATP1B3, OATP2B1, PEPT1 and OCTN1 was investigated in vitro. Results of this study showed that neither peptide is an inhibitor of the common efflux and uptake transporters studied at clinically relevant concentrations.

The effect of linaclotide and its metabolites to inhibit the common intestinal enzymes (CYP2C9 and CYP3A4) and liver enzymes (CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4) or to induce liver enzymes (CYP1A2, 2B6, and 3A4/5) was investigated in vitro. Results of these studies showed that linaclotide and des-tyrosine metabolite are not inhibitors or inducers of the cytochrome P450 enzyme system.

Elimination

Following a single oral dose of 2,897 micrograms linaclotide on day 8, after a 7-day course of 290 micrograms/day in 18 healthy volunteers, approximately 3 to 5% of the dose was recovered in the faeces, virtually all of it as the des-tyrosine active metabolite.

Age and gender

Clinical studies to determine the impact of age and gender on the clinical pharmacokinetics of linaclotide have not been conducted because it is rarely detectable in plasma. Gender is not expected to have any impact on dosing.

Renal impairment

Linaclotide has not been studied in patients who have renal impairment. Linaclotide is rarely detectable in plasma, therefore, renal impairment would not be expected to affect clearance of the parent compound or its metabolite.

Hepatic impairment

Linaclotide has not been studied in patients who have hepatic impairment. Linaclotide is rarely detectable in plasma and is not metabolised by liver cytochrome P450 enzymes, therefore, hepatic impairment would not be expected to affect the metabolism or clearance of the parent drug or its metabolite.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and development.