Irinotecan

Structural formula
General
Non-proprietary name	Irinotecan
other names	( S ) -4,11-Diethyl-3,4,12,14-tetrahydro-4-hydroxy-3,14-dioxo-1 H -pyrano [3 ', 4': 6,7] -indolizino [1, 2- b ] quinolin-9-yl- [1,4'-bipiperidine] -1'-carboxylate
Molecular formula	C 33 H 38 N 4 O 6 (irinotecan) C 33 H 38 N 4 O 6 HCl (irinotecan mono hydrochloride ) C 33 H 38 N 4 O 6 · HCl · 3H 2 O (irinotecan · monohydrochloride · trihydrate )
External identifiers / databases
CAS number 97682-44-5 (irinotecan) 100286-90-6 (irinotecan mono hydrochloride ) 136572-09-3 (irinotecan · monohydrochloride · tri hydrate ) 130144-33-1 [( RS ) -Irinotecan] EC number 691-567-9 ECHA InfoCard 100.219.260 PubChem 60838 ChemSpider 54825 DrugBank DB00762 Wikidata Q412197
Drug information
ATC code	L01 xx19
Drug class	Cytostatic
Mechanism of action	Topoisomerase I inhibitors
properties
Molar mass	586.68 g / mol (irinotecan) 623.14 g / mol (irinotecan monohydrochloride) 677.19 g / mol (irinotecan · monohydrochloride · tri hydrate )
Melting point	222–223 ° C (irinotecan) 256.5 ° C (irinotecan monohydrochloride trihydrate )
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302 P: no P-phrases
Toxicological data	867 mg kg −1 ( LD 50 ,  rat ,  oral , monohydrochloride)
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Irinotecan is a drug that is used to treat certain types of cancer . Pharmacologically, irinotecan is a cytostatic from the group of topoisomerase inhibitors , chemically it is a semi-synthetic derivative of the naturally occurring plant ingredient camptothecin . Camptothecin is an alkaloid that is obtained from the plant Camptotheca acuminata .

Mechanism of action

Irinotecan causes “programmed cell death” ( apoptosis ). It inhibits the enzyme DNA topoisomerase I, which regulates the spatial arrangement of DNA and is more active in many tumors. The pathologically increased cell division of the degenerate tissue is slowed down.

Irinotecan and its active metabolite SN-38 attach to the complex of DNA topoisomerase I and DNA and prevent the reclosure of the previously effected DNA single-strand break . According to current knowledge, the cause replication of DNA by the corresponding enzymes such as DNA polymerases in contact with the complex of irinotecan, DNA and DNA topoisomerase I has a double-strand break of the DNA and hence discontinuation of DNA replication . Mammalian cells do not have a sufficiently efficient DNA repair mechanism to repair such DNA double-strand breaks.

In terms of the cell cycle , irinotecan is only effective in the S phase of the cell cycle ( DNA synthesis ). Dormant cells (healthy and diseased) which do not synthesize any DNA, i.e. which are not in the S phase of the cell cycle, are not influenced by Irinotecan.

Related substances with the same mechanism of action are topotecan and camptothecin . Etoposide (VP16) and teniposide (VM26) are also topoisomerase inhibitors, but they inhibit DNA topoisomerase II.

Metabolism

Irinotecan is a prodrug . It is converted into the active and more lipophilic form SN-38 mainly in the liver by a carboxyesterase- mediated cleavage of the carbamate group to form the phenol . SN-38 is an approximately 1000 times stronger inhibitor of DNA topoisomerase I than irinotecan itself. The half-life of irinotecan is 14.2 (range 6–12) hours. The mean terminal elimination half-life of SN-38 is 10–20 hours. Irinotecan is 50% bound to plasma proteins, SN-38 to 95%. The time to peak irinotecan plasma concentrations is one to two hours.

Irinotecan is excreted mainly via glucuronidation of the active metabolite SN-38 to SN-38- glucuronide , which is 50-100 times less effective than unchanged SN-38. Despite glucuronidation, only a small amount of SN-38 (3%) is excreted in the urine. 11–20% of the irinotecan is excreted unchanged in the urine. 63.7 ± 6.8% of the irinotecan and SN-38 are excreted in the stool.

Both Irinotecan and SN-38 exist in a pH-dependent equilibrium of two forms: a lactone form and a hydroxy form. An acidic pH leads to an increased transition from the hydroxy form to a lactone form, a basic pH does the opposite. Only the lactone form of irinotecan and SN-38 are effective against cells and are therefore active. The hydroxy form has no effect and is therefore inactive. The extent to which SN-38 contributes to the anti-tumor effect (antineoplastic effect) of irinotecan has not yet been reliably clarified.

Application areas)

Metastatic colon / rectal cancer

Primary treatment ( first line )

Irinotecan is used in the primary treatment ( first line therapy) of metastatic colon carcinoma ( colon cancer with remote colonization; stage IV according to Dukes) in combination with 5-fluorouracil (5-FU) and folinic acid . The better efficacy of the combination of irinotecan, 5-FU and folinic acid compared to 5-FU and folinic acid alone has been demonstrated in two randomized , controlled, multinational clinical phase III studies.

Secondary treatment ( second line )

Irinotecan is used in the secondary treatment ( second line therapy) of metastatic colon carcinoma , which did not respond or only inadequately responded to primary treatment with 5-FU and folinic acid (example: growth of the tumor or metastases during therapy with 5-FU and Folinic acid or no regression of the tumor or metastases during therapy with 5-FU and folinic acid). The proof of effectiveness of Irinotecan is based on three open clinical multicenter studies with Irinotecan as the only substance tested against 5-FU infusions or best supportive therapy (no chemotherapy).

Experimental use

Irinotecan will be tested in the other of the therapy tumor diseases such as cervical cancer (cervical cancer), esophageal cancer (esophageal cancer), gastric carcinoma (stomach cancer), lung cancer (lung cancer), mesothelioma (pleural cancer), pancreatic cancer (pancreatic cancer), cholangiocarcinoma ; as well as in children and adolescents for the treatment of extracranial solid tumors (Ewing's sarcoma, neuroblastoma, rhabdomyosarcoma , PNET , Wilms tumor) or certain brain tumors (ependymoma, medulloblastoma , malignant glioma , glioblastoma, PNET).

administration

Irinotecan is infused slowly intravenously (over 90 minutes). If the combination treatment is indicated, the folinic acid infusion takes place immediately afterwards and then the 5-FU infusion.

The prophylactic administration of atropine (alleviation or prevention of a cholinergic syndrome) or antiemetics (against nausea and vomiting) may be indicated to prevent or alleviate the undesirable effects of irinotecan .

Contraindications and special precautions

Irinotecan should be used with

• previous irradiation in the area of ​​the abdomen and pelvis (irradiation of the intestine),
• existing or intended pregnancy and
• existing severe liver damage
• Meulengracht's disease (icterus intermittens juvenilis, familial jaundice)

can only be used after a strict risk-benefit analysis.

Since irinotecan is excreted in breast milk , breast-feeding should not be used during treatment. Irinotecan-containing medicines are not approved for children and adolescents.

Side effects

Depending on the dose and the rate of infusion, a cholinergic syndrome can occur, which manifests itself early (within 24 hours, so-called acute cholinergic syndrome ) in the occurrence of bradycardia ( drop in heart rate), flushing of the face , runny nose, tearing, sweating and diarrhea ( diarrhea ) or late (after 24 hours and later) associated with diarrhea (diarrhea). Other possible side effects include myelosuppression (manifested in neutropenia , anemia and thrombocytopenia ), alopecia , liver damage ( transaminases , hyperbilirubinemia , jaundice to liver failure ), renal impairment ( creatinine , sometimes kidney failure, particularly if accompanied by fluid loss due to diarrhea), hypersensitivity ( Hypersensitivity, allergic reaction), colitis , ileus ( inflammation of the bowel and intestinal obstruction ).

Diarrhea (diarrhea)

Diarrhea caused by irinotecan is characteristic.

"Early diarrhea" occurs during or shortly after the irinotecan infusion. They are caused by a cholinergic effect of irinotecan, which can be traced back to an inhibition of acetylcholinesterase (AChE). In most cases, this early diarrhea due to irinotecan is short-lived and rarely severe. Parallel to diarrhea, additional symptoms of cholinergic syndrome are often sweating, runny nose (runny nose), increased saliva production, tearing, facial flushing and increased bowel activity. The administration of atropine can alleviate or prevent these symptoms and thus also the diarrhea (prophylactic administration). The increased salivation, together with the increased gastric mucus, can lead to gagging effects and vomiting.

"Late diarrhea" occurs 24 hours after the irinotecan infusion or even later. These diarrhea are usually more severe, last longer and, without countermeasures, can also lead to life-threatening conditions due to massive loss of fluid and salt. As a guideline for severe diarrhea, more than 10 bowel movements per day or diarrhea with blood. In contrast to "early diarrhea", "late diarrhea" is caused by additional mechanisms: in addition to the cholinergic effect due to the blockage of acetylcholinesterase, the toxic effect of the drug on the mucous membrane of the intestine is also one of the causes of these side effects. People over 65 years of age are at a higher risk of developing diarrhea from irinotecan.

Interactions

The interactions between irinotecan and other medicinal products or food components result from the hepatic metabolism of irinotecan, especially via the cytochrome CYP3A4. Substances that are also metabolized via CYP3A4 can influence the breakdown and thus the effects and side effects of irinotecan.

A number of interactions of irinotecan with other drugs and food ingredients are currently known.

Various anti-epileptic drugs such as carbamazepine , phenobarbital and phenytoin probably lower the effects of irinotecan by increasing its clearance due to their influence on the cytochrome P450 system . To compensate for a loss of effectiveness of Irinotecan, either an increase in the dose of Irinotecan or a discontinuation of the anti-epileptic drugs is necessary. Long-term therapy with dexamethasone can also reduce the effects of irinotecan by increasing the clearance of irinotecan through various mechanisms, so that a dose adjustment may be necessary if administered simultaneously. Even St. John's wort decreases the potency of irinotecan. The plant ingredients promote the CYP3A4-mediated conversion of irinotecan to inactive metabolites, so that lower plasma levels of the active substance SN-38 result.

Diuretics such as furosemide , torasemide , etc. increase diarrhea , which is a side effect of irinotecan . The resulting possible dehydration (water loss ) can be increased by the diuretics.

Concomitant use of irinotecan and etoposide increases the risk of liver toxicity (damage to the liver). The combined use of irinotecan and prochlorperazine increases the undesirable occurrence of akathisia (unable to sit).

Trade names

Monopreparations

Arinotec (A), Axinotecan (D), Campto (D, A, CH), Camptosar (USA, CDN), numerous generics (D, A, CH)

literature

• Drengler RL et al .: Phase I and pharmacokinetic trial of oral irinotecan administered daily for 5 days every 3 weeks in patients with solid tumors. In: J. Clin. Oncol. 1999; 17 (2): 685-696. PMID 10080615
• Earle CC et al .: Two schedules of second-line irinotecan for metastatic colon carcinoma. In: Cancer . 2004 Dec 1; 101 (11): 2533-2539. PMID 15503310
• Grivicich I et al .: The irinotecan / 5-fluorouracil combination induces apoptosis and enhances manganese superoxide dismutase activity in HT-29 human colon carcinoma cells. In: Chemotherapy. 2005 May; 51 (2-3): 93-102. PMID 15886469
• Harel M et al .: The 3D structure of the anticancer prodrug CPT-11 with Torpedo californica acetylcholinesterase rationalizes its inhibitory action on AChE and its hydrolysis by butyrylcholinesterase and carboxylesterase. In: Chem Biol Interact . 2005 Dec 15; 157-158: 153-157. PMID 16289500
• Hyatt JL et al .: Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11. In: Chem Biol Interact. 2005 Dec 15; 157-158: 247-252. PMID 16257398
• Ji SH et al .: Phase II study of irinotecan, 5-fluorouracil and leucovorin as first-line therapy for advanced colorectal cancer. In: Japanese Journal of Clinical Oncology . 2005 Apr; 35 (4): 214-217. PMID 15845571
• Ohtsu T et al .: Unexpected hepatotoxicities in patients with non-Hodgkin's lymphoma treated with irinotecan (CPT-11) and etoposide. In: Japanese Journal of Clinical Oncology. 1998 Aug; 28 (8): 502-506. PMID 9769785
• Rothenberg ML et al .: Alternative dosing schedules for irinotecan. In: Oncology (New York) . 1998; 12 (8 Suppl 6): 68-71. PMID 9726095
• Chabot GG .: Clinical Pharmacokinetics of irinotecan. In: Clin Pharmacokinet . 1997; 33 (4): 245-259. PMID 9342501
• Slatter JG et al .: Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following IV infusion of [(14) C] CPT-11 in cancer patients. In: Drug Metab Dispos . 2000; 28 (4): 423-433. PMID 10725311
• Slatter JG et al .: Bioactivation of the anticancer agent CPT-11 to SN-38 by human hepatic microsomal carboxylesterases and the in vitro assessment of potential drug interactions. In: Drug Metab Dispos. 1997 Oct; 25 (10): 1157-1164. PMID 9321519
• Tsavaris N et al .: Two different schedules of irinotecan (CPT-11) in patients with advanced colorectal carcinoma relapsing after a 5-fluorouracil and leucovorin combination. A randomized study. In: Cancer Chemother Pharmacol . 2003 Dec; 52 (6): 514-519. PMID 14504920
• Yoshimatsu K et al .: Second-line chemotherapy with low-dose CPT-11 and cisplatin for colorectal cancer resistant to 5-FU-based chemotherapy. In: Cancer Chemother Pharmacol. 2003 Dec; 52 (6): 465-468. PMID 12920569

Individual evidence

1. ↑ Entry on irinotecan. In: Römpp Online . Georg Thieme Verlag, accessed on June 1, 2014.
2. ^ The Merck Index : An Encyclopedia of Chemicals, Drugs, and Biologicals, 14th Edition (Merck & Co., Inc.), Whitehouse Station, NJ, USA, 2006; Pp. 885-886, ISBN 978-0-911910-00-1 .
3. ↑ ^{a b c} Data sheet Irinotecan hydrochloride from Sigma-Aldrich , accessed on April 6, 2011 ( PDF ).

Web links

• Drug Prescription Information at FDA (PDF file; 342 kB) US package insert for irinotecan (Camptosar®). Status: May 14, 2010, freely accessible.
• British Columbia Cancer Agency information on irinotecan Comprehensive, clinically oriented monograph on irinotecan. Status: February 1, 2006, freely accessible.

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