Chemical formula: C₁₆₄H₂₅₂N₄₄O₅₅S Molecular mass: 3,750.803 g/mol
The naturally occurring human glucagon-like peptide-2 (GLP-2) is a peptide secreted by L cells of the intestine which is known to increase intestinal and portal blood flow, inhibit gastric acid secretion, and decrease intestinal motility. Teduglutide is an analogue of GLP-2. In several nonclinical studies, teduglutide has been shown to preserve mucosal integrity by promoting repair and normal growth of the intestine through an increase of villus height and crypt depth.
Similar to GLP-2, teduglutide is 33 amino acids in length with an amino acid substitution of alanine by glycine at the second position of the N-terminus. The single amino acid substitution relative to naturally occurring GLP-2 results in resistance to in vivo degradation by the enzyme dipeptidyl peptidase-IV (DPP-IV), resulting in an extended half-life. Teduglutide increases villus height and crypt depth of the intestinal epithelium.
Based on the findings derived from pre-clinical studies (see sections 4.4 and 5.3) and the proposed mechanism of action with the trophic effects on intestinal mucosa, there appears to be a risk for the promotion of small intestinal and/or colonic neoplasia. The clinical studies conducted could neither exclude nor confirm such an increased risk. Several cases of benign colorectal polyps occurred during the course of the trials, however, the frequency was not increased compared to placebo-treated patients. In addition to the need for a colonoscopy with removal of polyps by the time of the initiation of the treatment, every patient should be assessed for the need of an enhanced surveillance schedule based on the patient characteristics (e.g., age and underlying disease, previous occurrence of polyps etc.).
Teduglutide was rapidly absorbed from subcutaneous injection sites with maximum plasma levels occurring approximately 3-5 hours after dose administration at all dose levels. The absolute bioavailability of subcutaneous teduglutide is high (88%). No accumulation of teduglutide was observed following repeated subcutaneous administration.
Following subcutaneous administration, teduglutide has an apparent volume of distribution of 26 litres in patients with SBS.
The metabolism of teduglutide is not fully known. Since teduglutide is a peptide it is likely that it follows the principal mechanism for peptide metabolism.
Teduglutide has a terminal elimination half-life of approximately 2 hours. Following intravenous administration teduglutide plasma clearance was approximately 127 ml/hr/kg which is equivalent to the glomerular filtration rate (GFR). Renal elimination was confirmed in a study investigating pharmacokinetics in subjects with renal impairment. No accumulation of teduglutide was observed following repeated subcutaneous administrations.
The rate and extent of absorption of teduglutide is dose-proportional at single and repeated subcutaneous doses up to 20 mg.
Following subcutaneous administration, similar Cmax of teduglutide across age groups was demonstrated by population pharmacokinetics modelling. However, lower exposure (AUC) and shorter half-life were seen in paediatric patients 1 to 17 years of age, as compared with adults. The pharmacokinetic profile of teduglutide in this paediatric population, as evaluated by clearance and volume of distribution, was different from that observed in adults after correcting for body weights. Specifically, clearance decreases with increasing age from 1 year old to adults. No data are available for paediatric patients with moderate to severe renal impairment and end-stage renal disease (ESRD).
No clinically relevant gender differences were observed in clinical studies.
In a phase 1 study no difference in pharmacokinetics of teduglutide could be detected between healthy subjects younger than 65 years versus older than 65 years. Experience in subjects 75 years and above is limited.
In a phase 1 study the effect of hepatic impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 20 mg teduglutide was investigated. The maximum exposure and the overall extent of exposure to teduglutide following single 20 mg subcutaneous doses were lower (10-15%) in subjects with moderate hepatic impairment relative to those in healthy matched controls.
In a phase 1 study, the effect of renal impairment on the pharmacokinetics of teduglutide following subcutaneous administration of 10 mg teduglutide was investigated. With progressive renal impairment up to and including end-stage renal disease the primary pharmacokinetic parameters of teduglutide increased up to a factor of 2.6 (AUCinf) and 2.1 (Cmax) compared to healthy subjects.
Hyperplasia in the gall bladder, hepatic biliary ducts, and pancreatic ducts were observed in subchronic and chronic toxicology studies. These observations were potentially associated with the expected intended pharmacology of teduglutide and were to a varying degree reversible within an 8-13 week recovery period following chronic administration.
In pre-clinical studies, severe granulomatous inflammations were found associated with the injection sites.
Teduglutide was negative when tested in the standard battery of tests for genotoxicity.
In a rat carcinogenicity study, treatment related benign neoplasms included tumours of the bile duct epithelium in males exposed to teduglutide plasma levels approximately 32- and 155-fold higher than obtained in patients administered the recommended daily dose (incidence of 1 out of 44 and 4 out of 48, respectively). Adenomas of the jejunal mucosa were observed in 1 out of 50 males and 5 out of 50 males exposed to teduglutide plasma levels approximately 10- and 155-fold higher than obtained in patients administered the recommended daily dose. In addition, a jejunal adenocarcinoma was observed in a male rat administered the lowest dose tested (animal:human plasma exposure margin of approximately 10-fold).
Reproductive and developmental toxicity studies evaluating teduglutide have been carried out in rats and rabbits at doses of 0, 2, 10 and 50 mg/kg/day subcutaneously. Teduglutide was not associated with effects on reproductive performance, in utero or developmental parameters measured in studies to investigate fertility, embryo-foetal development and pre- and post-natal development. Pharmacokinetic data demonstrated that the teduglutide exposure of foetal rabbits and suckling rat pups was very low.
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