The metabolic and excretion patterns were highly similar across species with liraglutide being fully metabolised in the body by sequential cleavage of small peptide fragments and amino acids. The in vitro metabolism studies indicate that the initial metabolism involves cleavage of the peptide backbone with no degradation of the glutamate-palmitic acid side-chain. Mice, rats and monkeys displayed similar plasma profiles and showed no significant gender differences. A higher number of metabolites were observed in plasma from the animal species (especially the rat and monkey) as compared to human plasma. This disparity can partly be explained by differences in the sample preparation as human plasma samples were freeze dried prior to analysis causing a removal of volatile metabolites (including tritiated water). All detected metabolites were minor and obtained in low amount (<15%) and therefore no structural identification of these was performed. This is acceptable since the metabolites are only formed in low amounts and since the metabolites are expected to resemble endogenous substances with well-known metabolic pathways
During the initial 24 hours following administration of a single 3(H)-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized /SRP: in a manner similar to large proteins/ without a specific organ as a major route of elimination.
IDENTIFICATION AND USE: Liraglutide is a clear colorless liquid formulated into solution for subcutaneous use. Liraglutide is a synthetic, long-acting human glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic). It is used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. HUMAN EXPOSURE AND TOXICITY: Overdoses have been reported in clinical trials and post-marketing use of liraglutide. Effects have included severe nausea and severe vomiting. Post-marketing reports also include acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema), and acute renal failure and worsening of chronic renal failure (which may require hemodialysis). Liraglutide also causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether liraglutide causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Therefore, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) and in patients with multiple endocrine neoplasia syndrome type 2 (MEN 2). Finally, there are no adequate and well-controlled studies of liraglutide in pregnant women; however the drug did cause developmental toxicity in experimental animals. Therefore, liraglutide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. ANIMAL STUDIES: Liraglutide had no adverse effects on fertility when given to male rats at doses up to 1.0 mg/kg/day. However, liraglutide caused developmental toxicity in both rats and rabbits. When female rats were given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day, the number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidences of fetal malformations in liraglutide-treated groups were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. In a rabbit developmental study, pregnant females were administered liraglutide subcutaneously at doses of 0.01, 0.025 and 0.05 mg/kg/day from gestation day 6 through day 18 inclusive. Fetal weight was decreased and the incidence of total major fetal abnormalities was increased at all dose levels tested. Single cases of microphthalmia were noted at all dose levels. In addition, there was an increase in the fetal incidence of connected parietals in the high dose group, and a single case of split sternum in the 0.025 and 0.05 mg/kg/day. Minor abnormalities considered to be treatment-related were an increase in the incidence of jugal(s) connected/fused to maxilla at all dose levels and an increase in the incidence of bilobed/bifurcated gallbladder at 0.025 and 0.50 mg/kg/day. Studies for the carcinogenicity potential of liraglutide were also conducted in mice and rats. In both species, a dose-related increase in benign thyroid C-cell adenomas and malignant C-cell carcinomas were observed. Also, there was a treatment-related increase in the incidence and severity of focal C-cell hyperplasia in both male and female rats. In addition, there was a treatment-related increase in fibrosarcomas on the dorsal skin and subcutis, the body surface used for drug injection, in male mice. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. Finally, liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats.
In large clinical trials, serum enzyme elevations were no more common with liraglutide therapy than with placebo or comparator agents, and no instances of clinically apparent liver injury were reported. Since licensure, there has been a single case report of autoimmune hepatitis arising in a patient taking liraglutide. She did not improve with stopping liraglutide and ultimately required long term corticosteroid therapy, suggesting that the autoimmune hepatitis was independent of the drug therapy or that liraglutide triggered an underlying condition. Other cases of hepatotoxicity due to liraglutide have not been published and the product label does not list liver injury as an adverse event. Thus, liver injury due to liraglutide must be quite rare.
A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza at steady state. Victoza lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of Victoza on the overall exposure (AUC) of ethinylestradiol. Victoza increased the levonorgestrel AUC0-8 by 18%. Victoza delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 hr.
A single dose of digoxin 1 mg was administered 7 hours after the dose of Victoza at steady state. The concomitant administration with Victoza resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 hr to 1.5 hr.
A single dose of lisinopril 20 mg was administered 5 minutes after the dose of Victoza at steady state. The co-administration with Victoza resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 hr to 8 hr with Victoza.
The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%).
Following a 3(H)-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/hr with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration.
Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng hr/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-8 was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-8 from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.
Liraglutide is a novel once-daily human glucagon-like peptide (GLP)-1 analog in clinical use for the treatment of type 2 diabetes. To study metabolism and excretion of 3(H)-liraglutide, a single subcutaneous dose of 0.75 mg/14.2 MBq was given to healthy males. The recovered radioactivity in blood, urine, and feces was measured, and metabolites were profiled. In addition, 3(H)-liraglutide and [(3)H]GLP-1(7-37) were incubated in vitro with dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) to compare the metabolite profiles and characterize the degradation products of liraglutide. The exposure of radioactivity in plasma (area under the concentration-time curve from 2 to 24 hr) was represented by liraglutide (> or = 89%) and two minor metabolites (totaling < or =11%). Similarly to GLP-1, liraglutide was cleaved in vitro by DPP-IV in the Ala8-Glu9 position of the N terminus and degraded by NEP into several metabolites. The chromatographic retention time of DPP-IV-truncated liraglutide correlated well with the primary human plasma metabolite [GLP-1(9-37)], and some of the NEP degradation products eluted very close to both plasma metabolites. Three minor metabolites totaling 6 and 5% of the administered radioactivity were excreted in urine and feces, respectively, but no liraglutide was detected. In conclusion, liraglutide is metabolized in vitro by DPP-IV and NEP in a manner similar to that of native GLP-1, although at a much slower rate. The metabolite profiles suggest that both DPP-IV and NEP are also involved in the in vivo degradation of liraglutide. The lack of intact liraglutide excreted in urine and feces and the low levels of metabolites in plasma indicate that liraglutide is completely degraded within the body.
来源:Hazardous Substances Data Bank (HSDB)
文献信息
NOVEL COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING INSULIN RESISTANCE
申请人：UNIVERSITE PARIS DESCARTES
公开号：US20200030297A1
公开（公告）日：2020-01-30
The invention relates to a compound inhibiting the interaction between a Grb14 protein and an insulin receptor of Formula (I) or Formula (II),
their salts, solvates, and/or diastereoisomers, for use for therapeutic purposes, in particular for the treatment of insulin resistance, and to pharmaceutical compositions containing such compounds.
Compounds, compositions and methods for treating insulin resistance
申请人：UNIVERSITE PARIS DESCARTES
公开号：US11020378B2
公开（公告）日：2021-06-01
The invention relates to a compound inhibiting the interaction between a Grb14 protein and an insulin receptor of Formula (I) or Formula (II),
their salts, solvates, and/or diastereoisomers, for use for therapeutic purposes, in particular for the treatment of insulin resistance, and to pharmaceutical compositions containing such compounds.
NOUVEAUX COMPOSES, COMPOSITIONS ET METHODES POUR LE TRAITEMENT DE LA RESISTANCE A L'INSULINE
申请人：Université Paris Diderot
公开号：EP3600296A1
公开（公告）日：2020-02-05
[EN] NOVEL COMPOUNDS, COMPOSITIONS AND METHODS FOR TREATING INSULIN RESISTANCE<br/>[FR] NOUVEAUX COMPOSES, COMPOSITIONS ET METHODES POUR LE TRAITEMENT DE LA RESISTANCE A L'INSULINE
申请人：UNIV PARIS DIDEROT
公开号：WO2018172306A1
公开（公告）日：2018-09-27
L'invention porte sur un composé inhibiteur de l'interaction entre une protéine Grb14 et un récepteur de l'insuline de formule (I) ou de formule (II), leurs sels, solvates et/ou diastéréoisomères, pour une utilisation à des fins thérapeutiques, en particulier pour le traitement de l'insulinorésistance, et des compositions pharmaceutiques contenant de tels composés.
