Dasiglucagon

Dasiglucagon, sold under the brand name Zegalogue, is a medication used to treat severe hypoglycemia in people with diabetes.[1][2]

Dasiglucagon
Clinical data
Trade namesZegalogue
AHFS/Drugs.comZegalogue
License data
Routes of
administration		Subcutaneous
Drug classGlucagon receptor agonist
ATC code
Legal status
Legal status
Identifiers
IUPAC name
  • (4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxypropanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-carboxypropanoyl]amino]-2-methylpropanoyl]amino]propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-4-carboxy-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid
CAS Number
PubChem CID
DrugBank
UNII
KEGG
Chemical and physical data
FormulaC152H222N38O50
Molar mass3381.664 g·mol−1
3D model (JSmol)
SMILES
  • C[C@H]([C@@H](C(=O)N[C@@H](CC1=CC=CC=C1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)NC(C)(C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC4=CC=CC=C4)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC5=CNC6=CC=CC=C65)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)O)NC(=O)CNC(=O)[C@H](CCC(=O)N)NC(=O)[C@H](CO)NC(=O)[C@H](CC7=CNC=N7)N)O
InChI
  • InChI=1S/C152H222N38O50/c1-73(2)55-99(133(222)171-98(47-51-116(206)207)132(221)183-111(71-194)144(233)189-122(80(11)197)149(238)239)174-137(226)105(61-85-65-161-91-32-21-20-31-89(85)91)178-129(218)93(34-23-25-53-154)172-146(235)119(75(5)6)187-139(228)103(57-81-27-16-14-17-28-81)176-131(220)97(46-50-115(204)205)170-130(219)96(45-49-114(202)203)167-123(212)76(7)164-127(216)94(35-26-54-160-151(157)158)166-124(213)77(8)165-150(240)152(12,13)190-145(234)107(64-118(210)211)180-134(223)100(56-74(3)4)173-135(224)101(59-83-36-40-87(198)41-37-83)175-128(217)92(33-22-24-52-153)168-142(231)109(69-192)184-136(225)102(60-84-38-42-88(199)43-39-84)177-138(227)106(63-117(208)209)179-143(232)110(70-193)185-148(237)121(79(10)196)188-140(229)104(58-82-29-18-15-19-30-82)181-147(236)120(78(9)195)186-113(201)67-162-126(215)95(44-48-112(156)200)169-141(230)108(68-191)182-125(214)90(155)62-86-66-159-72-163-86/h14-21,27-32,36-43,65-66,72-80,90,92-111,119-122,161,191-199H,22-26,33-35,44-64,67-71,153-155H2,1-13H3,(H2,156,200)(H,159,163)(H,162,215)(H,164,216)(H,165,240)(H,166,213)(H,167,212)(H,168,231)(H,169,230)(H,170,219)(H,171,222)(H,172,235)(H,173,224)(H,174,226)(H,175,217)(H,176,220)(H,177,227)(H,178,218)(H,179,232)(H,180,223)(H,181,236)(H,182,214)(H,183,221)(H,184,225)(H,185,237)(H,186,201)(H,187,228)(H,188,229)(H,189,233)(H,190,234)(H,202,203)(H,204,205)(H,206,207)(H,208,209)(H,210,211)(H,238,239)(H4,157,158,160)/t76-,77-,78+,79+,80+,90-,92-,93-,94-,95-,96-,97-,98-,99-,100-,101-,102-,103-,104-,105-,106-,107-,108-,109-,110-,111-,119-,120-,121-,122-/m0/s1
  • Key:RZRMFQMNPDPAIX-AJTOSFMRSA-N

Dasiglucagon is generally well tolerated when used to treat severe hypoglycemia in patients with T1DM in phase III trials. In adults, the most common side effects occurring within 12 h of treatment in ≥ 2% of dasiglucagon recipients and at a higher frequency than with placebo is nausea (57 vs. 4%), vomiting (25 vs. 2%), headache (11 vs. 4%), diarrhea (5 vs. 0%), and injection site pain (2 vs. 0%). Common side effects were seen in pediatric patients: nausea (65 vs. 0%), vomiting (50 vs. 0%), headache (10 vs 0%), and injection site pain (5 vs 0%). Other adverse effects occurring within 12 h of treatment with dasiglucagon include bradycardia, hypertension, hypotension, orthostatic intolerance, palpitations, and presyncope.[3]

The novel glucagon analog dasiglucagon was started by Glostrup and Beta Bionics on June 22, 2017. [3][4] Subsequently, on July 3, 2017, Glostrup announced the commencement of a phase 3 trial for dasiglucagon.[4] On December 7, 2017, Zealand (Copenhagen, Denmark) announced the initiation of a phase 3 pivotal trial for dasiglucagon, with the intention of submitting positive outcomes to the FDA in 2019.[5] Dasiglucagon was approved for medical use in the United States in March 2021.[1][6][3][7] It was designated an orphan drug in August 2017.[8]

Medical uses

Dasiglucagon is indicated for the treatment of severe hypoglycemia in people aged six years of age and older with diabetes.[1][6] Dasiglucagon is available as a solution for subcutaneous injection in a single-use autoinjector or prefilled syringe.[5] The recommended dose is 0.6 mg administered into the outer upper arm, lower abdomen, buttocks, or thigh. If no response is observed after 15 min, a second 0.6 mg dose from a new device may be administered while waiting for emergency assistance.[3]

Contraindications

Dasiglucagon is contraindicated in people with pheochromocytoma or insulinoma.[1]

Pharmacodynamics

Dasiglucagon elevates blood glucose levels in normal and hypoglycemic conditions.[9] In adult patients with type 1 diabetes, the average increase in glucose levels at 90 minutes after dasiglucagon administration was 168 mg/dL. For pediatric patients aged seven to 17 years with type 1 diabetes, the mean glucose increase at 60 minutes post-administration was 162 mg/dL.[10] A study conducted on Danish patients with type 1 diabetes (T1DM) compared the pharmacological effects of dasiglucagon with glucagon. Dasiglucagon reached its maximum plasma concentration later than glucagon (35 minutes vs. 20 minutes) across different doses. The time for patients to recover glycemic levels above 70 mg/dL was similar between dasiglucagon (≥0.3 mg) and glucagon (0.5 mg and 1 mg) groups.[11] Dasiglucagon rapidly increased plasma glucose (PG) levels in a dose-dependent manner, reaching a maximum concentration in approximately 50-90 minutes. The glycokinetic response of dasiglucagon was 2-4 times higher than that of glucagon.[12] Dasiglucagon had a higher overall effect than GlucaGen at certain dose levels. In children with T1DM (7 to 17 years old), dasiglucagon showed a faster increase in blood glucose levels by 160 mg/dL or more from baseline at an earlier time (about 30 min) than in adults.[13] Due to the limited number of patients aged 65 years and older enrolled in phase 3 trials, it was impossible to determine if these patients' responses differed from those of young adults. Dasiglucagon demonstrates pharmacological effects consistent with glucagon, except for the freezing deficiency observed in rats (specific to rats and occurring simultaneously with glucagon and dasiglucagon) and the accumulation of liver glycogen in non-diabetic animals with obvious hyperglycemia and hyperinsulinemia.[14]

Pharmacokinetics

Dasiglucagon rapidly enters the bloodstream upon administration, resulting in a dose-dependent increase in plasma levels within approximately 15 minutes.[4][12] The maximum concentration of dasiglucagon in the bloodstream is typically attained around 35 minutes after administration, with a half-life (t1/2) of approximately 0.5 hours. Following the time to maximum concentration (tmax), dasiglucagon demonstrates a decline in concentration over a span of approximately 0.4-0.7 hours, as compared to glucagon's t1/2 of 0.25 hours. [15] Consequently, dasiglucagon exhibits significantly greater values for area under the curve (AUC) measurements, such as AUC0-inf, AUC0-30 min, AUC0-240 min, and maximum concentration (Cmax), when administered under euglycemic conditions. These values are approximately 1.4-4 times higher than those observed with glucagon.[12] Comparative analysis with the medication GlucaGen® (glucagon for injection 1mg/mL) reveals that dasiglucagon demonstrates more prolonged plasma exposure and higher total drug exposure (AUC0-inf). Therapeutic ratios for dasiglucagon doses of 0.6 mg and 0.3 mg, in relation to GlucaGen® doses of 1.0 mg and 0.5 mg, respectively, indicate superior effects on AUC0-inf, BL (1.59 and 1.46). In contrast, the effects on Cmax,BL are similar (1.03 and 0.91).[12][15] However, it is worth noting that the upper limit of the 95% confidence interval (CI) for Cmax and AUC0-30 min is slightly lower than 1, potentially due to higher early plasma exposure per milligram observed in the lower-dose group compared to the higher-dose group.[15] In clinical trials (NCT03216226), dasiglucagon showed a similar safety profile to reconstituted glucagon. No serious adverse events or deaths were reported. The most common side effects were nausea and vomiting. In terms of efficacy, dasiglucagon was as effective as reconstituted glucagon in reversing severe hypoglycemia induced by insulin, with a median recovery time of 10 minutes compared to 12 minutes for reconstituted glucagon. The recovery time was significantly shorter compared to the placebo group (median 40 minutes).[16]

Interactions

Dasiglucagon may cause temporary increases in blood pressure and pulse when taken concurrently with beta-blockers. When taken with indomethacin, dasiglucagon may lose its effectiveness in increasing blood sugar levels and potentially lead to hypoglycemia. Additionally, dasiglucagon has the potential to enhance the anticoagulant effect of warfarin. It is important to note that dasiglucagon interacts with 23 known medications.[10]

Mechanism of Action

Dasiglucagon operates through the same mechanism as endogenous glucagon, acting as an agonist at glucagon receptors expressed throughout the body, which are G-coupled receptors. Binding to liver glucagon receptors, dasiglucagon activates Gsα and Gq, resulting in the activation of adenylate cyclase. This, in turn, increases intracellular cyclic AMP levels, stimulating glycogenolysis and gluconeogenesis in the liver.[17] As glucose is primarily released from liver glycogen stores, the presence of glycogen stores in the liver is essential for dasiglucagon to exert its antihypoglycemic effects[10]

References
  1. "Zegalogue- dasiglucagon injection, solution". DailyMed. Retrieved 22 May 2021.
  2. Li S, Hu Y, Tan X, Wang D, Hu J, Zou P, Wang L (August 2020). "Evaluating dasiglucagon as a treatment option for hypoglycemia in diabetes". Expert Opinion on Pharmacotherapy. 21 (11): 1311–1318. doi:10.1080/14656566.2020.1747432. PMID 32267182. S2CID 215405434.
  3. "Zealand Pharma Announces FDA Approval of Zegalogue (dasiglucagon) injection, for the Treatment of Severe Hypoglycemia in People with Diabetes" (Press release). Zealand Pharma. 22 March 2021. Retrieved 22 March 2021 – via GlobeNewswire.
  4. Rentzepis PJ, Kurian MJ, Carracher AM, Close KL (December 2018). "Practical Ways to Achieve Targets in Diabetes Care". Journal of Diabetes. 10 (12): 911–915. doi:10.1111/1753-0407.12842. PMID 30120823. S2CID 52033703.
  5. Carracher AM, Marathe PH, Close KL (May 2018). "International Diabetes Federation 2017". Journal of Diabetes. 10 (5): 353–356. doi:10.1111/1753-0407.12644. PMID 29345068. S2CID 206942387.
  6. "Dasiglucagon: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 22 March 2021.
  7. Blair HA (June 2021). "Dasiglucagon: First Approval". Drugs. 81 (9): 1115–1120. doi:10.1007/s40265-021-01531-z. PMID 34047955. S2CID 235221008.
  8. "Dasiglucagon Orphan Drug Designations and Approvals". U.S. Food and Drug Administration (FDA). 10 August 2017. Retrieved 22 March 2021.
  9. Xu B, Tang G, Chen Z (December 2021). "Dasiglucagon: an effective medicine for severe hypoglycemia". European Journal of Clinical Pharmacology. 77 (12): 1783–1790. doi:10.1007/s00228-021-03183-0. PMID 34223944. S2CID 235733098.
  10. "FDA approves Zegalogue (dasiglucagon) injection for the treatment of severe hypoglycemia in people with diabetes" (PDF). 2021. Retrieved 6 June 2023.
  11. Hövelmann U (August 2018). "Dasiglucagon: lösungsstabiles, effektives und sicheres Glucagonanalogon". Diabetologie und Stoffwechsel (in German). 13 (3): 214. doi:10.1055/a-0609-9671. ISSN 1861-9002. S2CID 243926385.
  12. Hövelmann U, Olsen MB, Mouritzen U, Lamers D, Kronshage B, Heise T (March 2019). "Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus". Diabetes, Obesity & Metabolism. 21 (3): 601–610. doi:10.1111/dom.13562. PMC 6587565. PMID 30350477.
  13. "Zegalogue (dasiglucagon hydrochloride)". Drugs@FDA: FDA-Approved Drugs. Retrieved 6 June 2023.
  14. Castle JR, Elander M (February 2019). "Long-Term Safety and Tolerability of Dasiglucagon, a Stable-in-Solution Glucagon Analogue". Diabetes Technology & Therapeutics. 21 (2): 94–96. doi:10.1089/dia.2018.0363. PMID 30707621. S2CID 73431849.
  15. Hövelmann U, Bysted BV, Mouritzen U, Macchi F, Lamers D, Kronshage B, et al. (March 2018). "Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog". Diabetes Care. 41 (3): 531–537. doi:10.2337/dc17-1402. PMID 29273578. S2CID 3411307.
  16. Heller S, Battelino T, Bailey TS, Pieber TR, Hövelmann U, Plum-Mörschel L, et al. (May 2023). "Integrated safety and efficacy analysis of dasiglucagon for the treatment of severe hypoglycaemia in individuals with type 1 diabetes" (PDF). Diabetes, Obesity & Metabolism. 25 (5): 1351–1360. doi:10.1111/dom.14987. PMID 36692230. S2CID 256192794.
  17. Jiang G, Zhang BB (April 2003). "Glucagon and regulation of glucose metabolism". American Journal of Physiology. Endocrinology and Metabolism. 284 (4): E671–E678. doi:10.1152/ajpendo.00492.2002. PMID 12626323.
  • "Dasiglucagon". Drug Information Portal. U.S. National Library of Medicine.
  • Clinical trial number NCT03378635 for "A Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Type 1 Diabetes Subjects" at ClinicalTrials.gov
  • Clinical trial number NCT03688711 for "Trial to Confirm the Clinical Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in Subjects With T1DM" at ClinicalTrials.gov
  • Clinical trial number NCT03667053 for "Trial to Confirm the Efficacy and Safety of Dasiglucagon in the Treatment of Hypoglycemia in T1DM Children" at ClinicalTrials.gov
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.