Ixekizumab

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Ixekizumab
Monoclonal antibody
TypeWhole antibody
SourceHumanized
TargetInterleukin 17A (IL-17A)
Clinical data
Pronunciationix-ee-KIZ-ue-mab[1]
Trade namesTaltz
AHFS/Drugs.comMonograph
MedlinePlusa616025
License data
Pregnancy
category
Routes of
administration		Subcutaneous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60–81%[7]
MetabolismPresumably proteolysis
Elimination half-life13 days[8]
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC6492H10012N1728O2028S46
Molar mass146192.34 g·mol−1
 ☒NcheckY (what is this?)  (verify)

Ixekizumab, sold under the brand name Taltz, is an injectable medication for the treatment of autoimmune diseases. Chemically, it is a form of a humanized monoclonal antibody.[9] The substance acts by binding interleukin 17A and neutralizing it, reducing inflammation.[10][11]

The most common side effects include upper respiratory infections, injection site reactions and fungal (tinea) infections.[12]

The drug was developed by Eli Lilly and Co. and is approved for the treatment of plaque psoriasis in the European Union and the United States as of 2016.[6][13]

Medical uses

In the United States, ixekizumab is indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, active psoriatic arthritis, active ankylosing spondylitis, and active non-radiographic axial spondyloarthritis with objective signs of inflammation.[14] In the European Union it is indicated for the treatment of moderate-to-severe plaque psoriasis[6] and as a second-line therapy for active psoriatic arthritis.[6][10]

In studies, the drug reduced the Psoriasis Area and Severity Index by at least 75% (PASI75) in 82–89% of patients during the first three months of treatment (depending on the dosing scheme), and 40% of patients experienced a complete absence of psoriasis symptoms (PASI100). In the placebo group, PASI75 was reached in 4% of patients, and PASI100 in none; in the group of patients receiving etanercept, an older anti-psoriasis drug, PASI75 was reached in 48%. Until the 60th study week, 11–44% of ixekizumab treated patients relapsed (again, depending on the dosing scheme), as compared to 84% under placebo.[10][15]

Contraindications

The medication is contraindicated for patients with certain infections such as active tuberculosis.[10][contradictory]

Adverse effects

In studies, ixekizumab increased the rate of infections (27% of ixekizumab treated patients, compared to 23% under placebo), including severe ones (0.6% versus 0.4% under placebo). Other common side effects included injection site reactions such as redness and pain (13–17% versus 3%),[16] oropharyngeal pain (1%) and nausea (1–2%).[10] Other common adverse effects (≥5.0%) include nasopharyngitis, upper respiratory tract infection, arthralgia, headache, back pain, hypertension, bronchitis, diarrhea, sinusitis, and urinary tract infection.[17]

In a review of 18,025 patient years (n=6892 patients), no anaphylaxis was reported, no reactivation of tuberculosis, and low incidence rate of candida infection and serious infections was found. Incidence rates decreased or remained constant over time.[17]

Ixekizumab does not have an increased risk of adverse effects in the elderly.[18]

Overdose

Up to fourfold doses have been given in studies without causing serious side effects.[10]

Interactions

No interaction studies have been done. Ixekizumab and interleukin 17 are not known to interact with cytochrome P450 (CYP) liver enzymes. Since inflammation suppresses CYP activity, it is theorized that ixekizumab could neutralize this effect and lower blood plasma concentrations of drugs that are metabolized by CYP enzymes, such as warfarin.[10]

Pharmacology

Mechanism of action

Ixekizumab binds to interleukin 17 (IL-17A), a pro-inflammatory cytokine, and blocks its action. Among other things, IL-17A stimulates proliferation and activation of keratinocytes in the skin.[10] This mechanism is similar to that of another anti-psoriasis antibody, brodalumab, which binds to the interleukin-17 receptor.[19]

The antibody has affinity to the homodimer IL-17A and the heterodimer IL-17A/F, but not to other members of the interleukin 17 family.[10]

Pharmacokinetics

After subcutaneous injection, ixekizumab has a bioavailability of 60–81%;[7] bioavailability is higher in the thigh than the abdomen or arm.[7] Highest blood plasma concentrations are reached after four to seven days after a single dose.[8] With the usual dosing scheme (loading plus a dose every two weeks), steady state concentrations are reached in the eighth week on average.[10]

Like other antibodies, ixekizumab is probably degraded by proteolysis. Its elimination half-life is 14–18 days.[10][20] The volume of distribution is 7.11 L.[8] Mean clearance is 0.39 L/day.[8] There is no difference in rate of clearance between elderly and younger patients.[18] Increased body weight increases the volume of distribution and clearance rate.[8] Ixekizumab displays linear pharmacokinetics across doses.[20]

Pharmacokinetic data is similar for autoinjector pens and prefilled syringes.[7]

Chemistry

Ixekizumab is a complete monoclonal antibody of the subclass IgG4, consisting of two light chains and two heavy chains linked by disulfide bridges. Both heavy chains are glycosylated at the asparagine in position 296. In the hinge region, a serine is replaced by a proline to reduce formation of half-antibodies and heterodimers in the manufacturing process. The terminal lysine found in wild-type IgG4 is removed. The antibody is produced in Chinese hamster ovary cells.[9][21]

History

Clinical trials included a Phase II trial of patients with moderate to severe psoriasis,[19] and a Phase III open-label trial.[22][full citation needed]

Ixekizumab was approved by the US Food and Drug Administration (FDA) in March 2016, for the treatment of adults with moderate-to-severe plaque psoriasis[12] and by the European Medicines Agency (EMA) in April 2016.[6] The safety and efficacy of ixekizumab were established in three randomized, placebo-controlled clinical trials with a total of 3,866 participants with plaque psoriasis who were candidates for systemic or phototherapy therapy.[12] The FDA approved ixekizumab based on the evidence from three clinical trials of 1958 participants with moderate to severe psoriasis.[23] The trials were conducted in the US, Canada, Europe, Russia, Mexico, Chile, Argentina, Japan and Australia.[23]

In December 2017, the FDA approved it for active psoriatic arthritis.[24]

References

  1. ^ "12 Difficult-to-Pronounce Drug Names". Pharmacy Times. 7 February 2018. Archived from the original on 21 March 2018. Retrieved 22 March 2018.
  2. ^ "Ixekizumab (Taltz) Use During Pregnancy". Drugs.com. 27 November 2019. Retrieved 27 March 2020.
  3. ^ "Prescription medicines: registration of new chemical entities in Australia, 2016". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  4. ^ "Health Canada New Drug Authorizations: 2016 Highlights". Health Canada. 14 March 2017. Retrieved 7 April 2024.
  5. ^ "Taltz 80 mg solution for injection in pre-filled syringe - Summary of Product Characteristics (SmPC)". (emc). 21 August 2019. Retrieved 27 March 2020.
  6. ^ a b c d e "Taltz EPAR". European Medicines Agency (EMA). 2 May 2016. Retrieved 27 March 2020.
  7. ^ a b c d Vu, TT; Gooderham, M; Papp, K (November 2016). "Ixekizumab for treatment of adults with moderate-to-severe plaque psoriasis and psoriatic arthritis". Expert review of clinical pharmacology. 9 (11): 1423–1433. doi:10.1080/17512433.2016.1242409. PMID 27690669.
  8. ^ a b c d e Kiwalkar, S; Beier, S; Deodhar, A (October 2019). "Ixekizumab for treating ankylosing spondylitis". Immunotherapy. 11 (15): 1273–1282. doi:10.2217/imt-2019-0094. PMID 31530049.
  9. ^ a b "Statement On A Nonproprietary Name Adopted By The USAN Council: Ixekizumab" (PDF). American Medical Association.
  10. ^ a b c d e f g h i j k Haberfeld H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag.
  11. ^ Cai Y, Fleming C, Yan J (July 2013). "Dermal γδ T cells--a new player in the pathogenesis of psoriasis". International Immunopharmacology. 16 (3): 388–391. doi:10.1016/j.intimp.2013.02.018. PMID 23499509.
  12. ^ a b c "FDA approves new psoriasis drug Taltz". U.S. Food and Drug Administration (FDA) (Press release). 22 March 2016. Retrieved 27 March 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  13. ^ "Taltz (ixekizumab) Injection". U.S. Food and Drug Administration (FDA). 3 May 2016. Retrieved 27 March 2020.
  14. ^ "Taltz- ixekizumab injection, solution". DailyMed. 23 August 2019. Retrieved 27 March 2020.
  15. ^ Klement A (4 June 2016). "Taltz". Österreichische Apothekerzeitung (in German) (14/2016): 12.
  16. ^ Shear NH, Paul C, Blauvelt A, Gooderham M, Leonardi C, Reich K, et al. (February 2018). "Safety and Tolerability of Ixekizumab: Integrated Analysis of Injection-Site Reactions from 11 Clinical Trials". Journal of Drugs in Dermatology. 17 (2): 200–206. PMID 29462229.
  17. ^ a b Griffiths, CEM; Gooderham, M; Colombel, JF; Terui, T; Accioly, AP; Gallo, G; Zhu, D; Blauvelt, A (June 2022). "Safety of Ixekizumab in Adult Patients with Moderate-to-Severe Psoriasis: Data from 17 Clinical Trials with Over 18,000 Patient-Years of Exposure". Dermatology and therapy. 12 (6): 1431–1446. doi:10.1007/s13555-022-00743-9. PMC 9209552. PMID 35624407. Retrieved 2 April 2024.
  18. ^ a b Di Lernia, Vito; Goldust, Mohamad (3 August 2018). "An overview of the efficacy and safety of systemic treatments for psoriasis in the elderly". Expert Opinion on Biological Therapy. 18 (8): 897–903. doi:10.1080/14712598.2018.1504016. ISSN 1471-2598. PMID 30032682. Retrieved 2 April 2024.
  19. ^ a b "Neue Antikörper in der Pipeline". Pharmazeutische Zeitung (in German) (12). 2012.
  20. ^ a b Dyring-Andersen, B; Skov, L; Zachariae, C (April 2015). "Ixekizumab for treatment of psoriasis". Expert review of clinical immunology. 11 (4): 435–42. doi:10.1586/1744666X.2015.1023295. PMID 25748485.
  21. ^ "Assessment report: Taltz" (PDF). European Medicines Agency. 25 February 2016. p. 7.
  22. ^ Clinical trial number NCT01624233 for "A Study in Japanese Participants With Moderate-to-Severe Psoriasis" at ClinicalTrials.gov
  23. ^ a b "Drug Trials Snapshots: Taltz". U.S. Food and Drug Administration (FDA). 22 March 2016. Retrieved 24 September 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  24. ^ "FDA approves Taltz for psoriatic arthritis in adults". Healio. 4 December 2017. Retrieved 23 September 2020.
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