irinotecan

Its main use is in colon cancer, in particular, in combination with other chemotherapy agents.{{cite web | title=Camptosar- irinotecan hydrochloride injection, solution | website=DailyMed | date=10 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e518dfc6-7e93-4fee-a66c-51e1ab71c056 | access-date=25 May 2020}} This includes the regimen FOLFIRI, which consists of infusional 5-fluorouracil, leucovorin, and irinotecan. The regimen XELIRI consists of capecitabine and irinotecan.{{cite journal | vauthors = Guo Y, Shi M, Shen X, Yang C, Yang L, Zhang J | title = Capecitabine plus irinotecan versus 5-FU/leucovorin plus irinotecan in the treatment of colorectal cancer: a meta-analysis | journal = Clinical Colorectal Cancer | volume = 13 | issue = 2 | pages = 110–118 | date = June 2014 | pmid = 24461997 | doi = 10.1016/j.clcc.2013.12.004 }}{{cite journal | vauthors = Kotaka M, Xu R, Muro K, Park YS, Morita S, Iwasa S, Uetake H, Nishina T, Nozawa H, Matsumoto H, Yamazaki K, Han SW, Wang W, Ahn JB, Deng Y, Cho SH, Ba Y, Lee KW, Zhang T, Satoh T, Buyse ME, Ryoo BY, Shen L, Sakamoto J, Kim TW | title = Study protocol of the Asian XELIRI ProjecT (AXEPT): a multinational, randomized, non-inferiority, phase III trial of second-line chemotherapy for metastatic colorectal cancer, comparing the efficacy and safety of XELIRI with or without bevacizumab versus FOLFIRI with or without bevacizumab | journal = Chinese Journal of Cancer | volume = 35 | issue = 1 | pages = 102 | date = December 2016 | pmid = 28007025 | pmc = 5178089 | doi = 10.1186/s40880-016-0166-3 | doi-access = free }}

It may also be used together with fluorouracil and folinic acid for pancreatic cancer following failure of initial treatment.{{cite web | title=Onivyde- irinotecan hydrochloride injection, powder, for solution | website=DailyMed | date=20 October 2017 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c8b58efa-1820-48a4-b70d-62918fc4abfc | access-date=25 May 2020}}

In February 2024, the US Food and Drug Administration (FDA) approved irinotecan liposome, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of metastatic pancreatic adenocarcinoma.{{cite web | title=FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma | website=U.S. Food and Drug Administration (FDA) | date=13 February 2024 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma | access-date=19 February 2024}} {{PD-notice}}

The most significant adverse effects of irinotecan include diarrhea, nausea and vomiting, neutropenia and fever, infections of blood or lungs (sepsis, pneumonia), shock, dehydration, kidney failure and thrombocytopenia (low levels of blood platelets).{{cite web | title=Onivyde pegylated liposomal EPAR | website=European Medicines Agency (EMA) | date=25 October 2016 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/onivyde-pegylated-liposomal | access-date=25 May 2020}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.{{cite web|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004125/WC500215029.pdf|title=Onivyde: EPAR – Product Information|publisher=European Medicines Agency|date=25 October 2016|url-status=live|archive-url=https://web.archive.org/web/20170116171738/http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/004125/WC500215029.pdf|archive-date=16 January 2017}}

Early diarrhea occurs during or shortly after the infusion of Irinotecan, and is usually transient and infrequently severe. Late diarrhea occurs more than 24 hours after administration of Irinotecan and can be life threatening, sometimes leading to severe dehydration requiring hospitalization or intensive care unit admission. This side-effect is managed with the aggressive use of antidiarrheals such as loperamide or atropine with the first loose bowel movement.{{cite book|title=Austria-Codex| veditors = Haberfeld H |at=Irinotecan Kabi 20 mg/ml Konzentrat zur Herstellung einer Infusionslösung|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2021|language=German}}Irinotecan {{Drugs.com|monograph|irinotecan}}. Accessed 18 September 2021.

The immune system is adversely impacted by irinotecan. This is reflected in lowered white blood cell counts in the blood, in particular the neutrophils.

Camptothecin, one of the four major structural classifications of plant-derived anti-cancerous compounds, is a cytotoxic alkaloid which consists of a pentacyclic ring structure containing a pyrrole (3, 4 β) quinoline moiety, an S-configured lactone form, and a carboxylate form.{{cite web|title=Nirmala, M. Joyce, A. Samundeeswari, and P. Deepa Sankar. 2011. "Natural Plant Resources in Anti-Cancer Therapy-A Review." Research in Plant Biology 1 (3): 1–14.|url=https://www.researchgate.net/publication/253181077}} Camptothecin is an inhibitor of topoisomerase I. Its analogue, irinotecan, is activated by hydrolysis to SN-38, and is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). The inhibition of topoisomerase I by the active metabolite SN-38 eventually leads to inhibition of both DNA replication and transcription.

The molecular action of irinotecan occurs by trapping a subset of topoisomerase-1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence.{{cite journal | vauthors = Pommier Y | title = Drugging topoisomerases: lessons and challenges | journal = ACS Chemical Biology | volume = 8 | issue = 1 | pages = 82–95 | date = January 2013 | pmid = 23259582 | pmc = 3549721 | doi = 10.1021/cb300648v }} One irinotecan molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the topoisomerase 1 enzyme.

{{IrinotecanPathway_WP229}}

Irinotecan can be administered by 30- or 90-minute intravenous infusions of either 125 mg/m² weekly for four of every six weeks or 350 mg/m² every three weeks.{{cite book | vauthors = Reyhanoglu G, Smith T | chapter =Irinotecan|date=2021| chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK554441/|title = StatPearls|place=Treasure Island (FL)|publisher=StatPearls Publishing|pmid=32119328|access-date=14 June 2021 }}

Irinotecan is a hydrophilic compound with a large volume of distribution (400 L/m²).{{cite journal | vauthors = de Man FM, Goey AK, van Schaik RH, Mathijssen RH, Bins S | title = Individualization of Irinotecan Treatment: A Review of Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics | journal = Clinical Pharmacokinetics | volume = 57 | issue = 10 | pages = 1229–1254 | date = October 2018 | pmid = 29520731 | pmc = 6132501 | doi = 10.1007/s40262-018-0644-7 }} At physiological pH, irinotecan and its active metabolite ethyl-10-hydroxy-camptothecin (SN-38) are present in two pH-dependent equilibrium isoforms; the anti tumor active lactone ring which hydrolyzed to the carboxylate isoform.

In plasma, the majority of irinotecan and SN-38 are bound to albumin, which stabilizes their lactone forms. In blood, irinotecan and SN-38 are bound to platelets and red blood cells.

Irinotecan has a linear pharmacokinetic. Population pharmacokinetic models assumed a three-compartmental model for irinotecan and a two-compartmental model for SN-38.

SN-38 has a short distribution half-life (approximately 8 min). It reached its peak plasma concentration within 2 h after infusion. Also SN-38 exhibit a second peak in the plasma concentration because of its enterohepatic re-circulation and its release from erythrocytes.

About 2–5% of the pro-drug irinotecan is hydrolyzed into its active metabolite SN-38 in the liver by two carboxylesterase converting enzymes (CES1 and CES2) and in plasma by butyrylcholinesterase (hBChE).{{cite journal | vauthors = Kciuk M, Marciniak B, Kontek R | title = Irinotecan-Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview | journal = International Journal of Molecular Sciences | volume = 21 | issue = 14 | pages = 4919 | date = July 2020 | pmid = 32664667 | pmc = 7404108 | doi = 10.3390/ijms21144919 | doi-access = free }} CES2 has a 12.5-fold higher affinity for irinotecan than CES1. While, butyrylcholinesterase has a 6-fold higher activity for irinotecan than CES. After conversion, SN-38 is actively transported to the liver by the organic anion transporting polypeptide (OATP) 1B1 transporter.

SN-38 is inactivated by glucuronidation to SN-38G (β-glucuronide conjugate) by several uridine diphosphate glucuronosyltransferase enzymes (UGTs) in the liver (UGT1A1, UGT1A9) and extra-hepatic (UGT1A1, UGT1A7, UGT1A10) and excreted into the bile. Several UGT polymorphisms affects irinotecan pharmacokinetics, for example, the decreased UGT1 activity, may lead to severe toxicity. Also, UGT1A1 conjugates bilirubin and bilirubin glucuronidation is another risk factor for increased toxicity

The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38.

Irinotecan is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC can be further converted by CES1 and CES2 in the liver to SN-38. Induction or inhibition of CYP3A enzymes by smoking, some herbs and medications may result in interactions with irinotecan.

Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2.

Irinotecan clearance is mainly biliary (66%) and estimated 12–21 L/h/m². All metabolites, except SN-38G, are mainly excreted in feces. Irinotecan elimination half-lives were reported between 5 and 18 h. SN-38 half-lives were reported between 6 and 32 h.

There is high (30%) interindividual variability in irinotecan pharmacokinetic parameters which can be altered by several factors including age, sex, dose, administration timing, hepatic function, enzyme activity or hematocrit levels.

Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.

People with variants of the UGT1A1 called TA₇, also known as the "*28 variant", express fewer UGT1A1 enzymes in their liver and often have Gilbert's syndrome. During chemotherapy, they effectively receive a larger than expected dose because their bodies are not able to clear irinotecan as fast as others. In studies this corresponds to higher incidences of severe neutropenia and diarrhea.{{cite journal | vauthors = Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch L, Ramírez J, Rudin CM, Vokes EE, Ratain MJ | title = Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan | journal = Journal of Clinical Oncology | volume = 22 | issue = 8 | pages = 1382–1388 | date = April 2004 | pmid = 15007088 | doi = 10.1200/JCO.2004.07.173 | doi-access = free }}

In 2004, a clinical study was performed that both validated prospectively the association of the *28 variant with greater toxicity and the ability of genetic testing in predicting that toxicity before chemotherapy administration.

In 2005, the FDA made changes to the labeling of irinotecan to add pharmacogenomics recommendations, such that irinotecan recipients with a homozygous (both of the two gene copies) polymorphism in UGT1A1 gene, to be specific, the *28 variant, should be considered for reduced drug doses. Irinotecan is one of the first widely used chemotherapy agents that is dosed according to the recipient's genotype.{{cite journal | vauthors = O'Dwyer PJ, Catalano RB | title = Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy | journal = Journal of Clinical Oncology | volume = 24 | issue = 28 | pages = 4534–4538 | date = October 2006 | pmid = 17008691 | doi = 10.1200/JCO.2006.07.3031 | doi-access = free }}

In February 2024, the FDA approved irinotecan liposome, in combination with oxaliplatin, fluorouracil, and leucovorin, for the first-line treatment of metastatic pancreatic adenocarcinoma. Efficacy was evaluated in NAPOLI 3 (NCT04083235), a randomized, multicenter, open-label, active-controlled trial in 770 participants with metastatic pancreatic adenocarcinoma who had not previously received chemotherapy in the metastatic setting. Randomization was stratified by region, liver metastases, and ECOG performance status. Participants were randomized (1:1) to receive one of the following treatments: NALIRIFOX: irinotecan liposome 50 mg/m2 as an intravenous infusion over 90 minutes, followed by oxaliplatin 60 mg/m2 as an intravenous infusion over 120 minutes, followed by leucovorin 400 mg/m2 intravenously over 30 minutes, followed by fluorouracil 2400 mg/m2 intravenously over 46 hours, every 2 weeks; Gem+NabP: Nab-paclitaxel 125 mg/m2 as an intravenous infusion over 35 minutes, followed by gemcitabine 1000 mg/m2 intravenously over 30 minutes on days 1, 8, and 15 of each 28-day cycle. The application was granted orphan drug designation.

Irinotecan received accelerated approval from the US Food and Drug Administration (FDA) in 1996,{{cite web | title=Camptosar: FDA-Approved Drugs | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&varApplNo=020571 | access-date=25 May 2020}} and full approval in 1998.{{cite web | title=Drug Approval Package: Camptosar (Irinotecan Hydrochloride) NDA# 20-571/S-008 | website=U.S. Food and Drug Administration (FDA) | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/020571s008.cfm | access-date=25 May 2020}}{{cite news |url=https://www.nytimes.com/1996/06/18/science/new-cancer-drug-approved.html |title=New Cancer Drug Approved |access-date=1 September 2017 |url-status=live |archive-url=https://web.archive.org/web/20160531010929/http://www.nytimes.com/1996/06/18/science/new-cancer-drug-approved.html |archive-date=31 May 2016 |newspaper=The New York Times |date=18 June 1996 }}{{cite letter | vauthors = Temple R |recipient= Walker JS |subject= New Drug Application |date= 22 October 1998 |url=http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20571s8ltr.pdf |access-date=26 July 2011 |url-status=live |archive-url=https://web.archive.org/web/20120130160455/http://www.accessdata.fda.gov/drugsatfda_docs/appletter/1998/20571s8ltr.pdf |archive-date=30 January 2012 | work = U.S. Food and Drug Administration (FDA) }}

A liposome encapsulated version of irinotecan sold under the brand name Onivyde, was approved by the FDA in October 2015, to treat metastatic pancreatic cancer.{{cite web | title=Onivyde | website=U.S. Food and Drug Administration (FDA) | date=29 September 2016 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/207793Orig1s000TOC.cfm | access-date=25 May 2020}}{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468654.htm|title=FDA approves new treatment for advanced pancreatic cancer|author=News Release|publisher=U.S. Food and Drug Administration (FDA)|date=22 October 2015|url-status=dead|archive-url=https://web.archive.org/web/20151024235715/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468654.htm|archive-date=24 October 2015}} It was approved for medical use in the European Union in October 2016.

During development, it was known as CPT-11.{{medical citation needed|date=May 2020}}

{{reflist}}

• {{cite book | title=Medical Genetics Summaries | chapter=Irinotecan Therapy and UGT1A1 Genotype | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK294473/ | veditors=Pratt VM, McLeod HL, Rubinstein WS, Scott SA, Dean LC, Kattman BL, Malheiro AJ | display-editors=3 | publisher=National Center for Biotechnology Information (NCBI) | year=2015 | pmid=28520360 | id=Bookshelf ID: NBK294473 | vauthors=Dean L | url=https://www.ncbi.nlm.nih.gov/books/NBK61999/ }}

• [http://www.pharmgkb.org/do/serve?objId=PA2001&objCls=Pathway Irinotecan Pathway on PharmGKB]

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