me: L-cysteinyl-L-cysteinyl-L-glutamyl-L-tyrosyl-L-cysteinyl-L-cysteinyl-L-asparaginyl-L-prolyl-L-alanyl-L-cysteinyl-L-threonyl-glycyl-L-cysteinyl-L-tyrosine, cyclic (1-6), (2-10), (5-13)-tris (disulfide).
The molecular formula of linaclotide is C59H79N15O21S6 and its molecular weight is 1526.8. The amino acid sequence for linaclotide is shown below:
Linaclotide is an amorphous, white to off-white powder. It is slightly soluble in water and aqueous sodium chloride (0.9%). LINZESS contains linaclotide-coated beads in hard gelatin capsules. LINZESS is available as 145 mcg and 290 mcg capsules for oral administration.
The inactive ingredients of LINZESS capsules include: calcium chloride dihydrate, L-leucine, hypromellose, microcrystalline cellulose, gelatin, and titanium dioxide.
1112 CLINICAL PHARMACOLOGY
11.112.1 Mechanism of Action
Linaclotide is a guanylate cyclase-C (GC-C) agonist. Both linaclotide 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 in 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, linaclotide has been shown to both accelerate GI transit and reduce intestinal pain. The linaclotide-induced reduction in visceral pain in animals is thought to be mediated by increased extracellular cGMP, which was shown to decrease the activity of pain-sensing nerves.
11.212.2 Pharmacodynamics
Although the pharmacologic effects of LINZESS in humans have not been fully eva luated, in clinical studies, LINZESS has been shown to change stool consistency as measured by the Bristol Stool Form Scale (BSFS) and increase stool frequency.
11.312.3 Pharmacokinetics
Absorption
LINZESS is minimally absorbed with low systemic availability following oral administration. Concentrations of linaclotide and its active metabolite in plasma are below the limit of quantitation after oral doses of 145 mcg or 290 mcg were administered. Therefore, standard pharmacokinetic parameters such as area under the curve (AUC), maximum concentration (Cmax), and half-life (t½) cannot be calculated.
Distribution
Given that linaclotide plasma concentrations following therapeutic oral doses are not measurable, linaclotide is expected to be minimally distributed to tissues.
Metabolism
Linaclotide is metabolized within the gastrointestinal tract to its principal, active metabolite by loss of the terminal tyrosine moiety. Both linaclotide and the metabolite are proteolytically degraded within the intestinal lumen to smaller peptides and naturally occurring amino acids.
Elimination
Active peptide recovery in the stool samples of fed and fasted subjects following the daily administration of 290 mcg of LINZESS for seven days averaged about 5% (fasted) and about 3% (fed) and virtually all as the active metabolite.
Food Effect
In a cross-over study, 18 healthy subjects were given LINZESS 290 mcg for 7 days both in the non-fed and fed state. Neither linaclotide nor its acti
