Irinotecan, sold under the brand name Camptosar among others, is a medication used to treat
colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
, and
small cell lung cancer
Small-cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix, prostate, and gastrointestinal tract. Compared to non-small cell car ...
.
[ For colon cancer it is used either alone or with ]fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, panc ...
.[ For small cell lung cancer it is used with ]cisplatin
Cisplatin is a chemotherapy medication used to treat a number of cancers. These include testicular cancer, ovarian cancer, cervical cancer, breast cancer, bladder cancer, head and neck cancer, esophageal cancer, lung cancer, mesothelioma, brain ...
.[ It is given intravenously.][
Common side effects include ]diarrhea
Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...
, vomiting, bone marrow suppression
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (t ...
, hair loss, shortness of breath, and fever.[ Other severe side effects include ]blood clots
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
, colon inflammation, and allergic reactions
Allergies, also known as allergic diseases, refer a number of conditions caused by the hypersensitivity of the immune system to typically harmless substances in the environment. These diseases include hay fever, food allergies, atopic dermati ...
.[ Those with two copies of the ]UGT1A1*28
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the ''UGT1A1'' gene.
UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...
gene variant are at higher risk for side effects.[ Use during pregnancy can result in harm to the baby.][ Irinotecan is a ]topoisomerase inhibitor
Topoisomerase inhibitors are chemical compounds that block the action of topoisomerases, which are broken into two broad subtypes: type I topoisomerases (TopI) and type II topoisomerases (TopII). Topoisomerase plays important roles in cellular rep ...
—it blocks the topoisomerase I
DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues i ...
enzyme, resulting in DNA damage and cell death
Cell death is the event of a biological cell ceasing to carry out its functions. This may be the result of the natural process of old cells dying and being replaced by new ones, as in programmed cell death, or may result from factors such as dis ...
.[
Irinotecan was approved for medical use in the United States in 1996.] It is on the World Health Organization's List of Essential Medicines. It is made from the natural compound camptothecin
Camptothecin (CPT) is a topoisomerase inhibitor. It was discovered in 1966 by M. E. Wall and M. C. Wani in systematic screening of natural products for anticancer drugs. It was isolated from the bark and stem of ''Camptotheca acuminata'' (Campto ...
which is found in the Chinese ornamental tree ''Camptotheca acuminata
''Camptotheca'' (happy tree, cancer tree, or tree of life) is a genus of medium-sized deciduous trees growing to tall, native to southern China and Tibet. The genus is usually included in the tupelo family Nyssaceae, but sometimes included (wit ...
''.[
]
Medical uses
Its main use is in colon cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
, in particular, in combination with other chemotherapy agents. This includes the regimen FOLFIRI FOLFIRI is a chemotherapy regimen for treatment of colorectal cancer. It is made up of the following drugs:
* FOL – folinic acid ( leucovorin), a vitamin B derivative used as a "rescue" drug for high doses of the drug methotrexate, but increases ...
, which consists of infusional 5-fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, panc ...
, leucovorin
Folinic acid, also known as leucovorin, is a medication used to decrease the toxic effects of methotrexate and pyrimethamine. It is also used in combination with 5-fluorouracil to treat colorectal cancer and pancreatic cancer, may be used to t ...
, and irinotecan. The regimen XELIRI consists of capecitabine
Capecitabine, sold under the brand name Xeloda among others, is a chemotherapy medication used to treat breast cancer, gastric cancer and colorectal cancer. For breast cancer it is often used together with docetaxel. It is taken by mouth.
Co ...
and irinotecan.
It may also be used together with fluorouracil and folinic acid for pancreatic cancer following failure of initial treatment.
Side effects
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).[ Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.]
Diarrhea
Irinotecan-associated diarrhea is severe and clinically significant, 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
Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given ...
with the first loose bowel movement.[Irinotecan . Accessed 2021-09-18.]
Immunosuppression
The immune system is adversely impacted by irinotecan. This is reflected in – sometimes dramatically – lowered white blood cell counts in the blood, in particular the neutrophils. The patient may experience neutropenia
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteri ...
(a clinically significant decrease of neutrophils in the blood).
Mechanism of action
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. Camptothecin is an inhibitor of topoisomerase I. Its analogue, irinotecan, is activated by hydrolysis to SN-38
SN-38 is an antineoplastic drug. It is the active metabolite of irinotecan (an analog of camptothecin - a topoisomerase I inhibitor) but has 1000 times more activity than irinotecan itself. In vitro cytotoxicity assays show that the potency of SN ...
, and is then inactivated by glucuronidation by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1
UDP-glucuronosyltransferase 1-1 also known as UGT-1A is an enzyme that in humans is encoded by the ''UGT1A1'' gene.
UGT-1A is a uridine diphosphate glucuronosyltransferase (UDP-glucuronosyltransferase, UDPGT), an enzyme of the glucuronidation pat ...
). 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
DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues i ...
-1-DNA cleavage complexes, those with a guanine +1 in the DNA sequence. One irinotecan molecule stacks against the base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the topoisomerase
DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Topological issues i ...
1 enzyme.
Interactive pathway
Pharmacokinetics
Administration
Irinotecan can be administrated 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.
Distribution
Irinotecan is a hydrophilic compound with a large volume of distribution (400 L/m2). 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.
Metabolism
Activation by carboxylesterases and butyrylcholinesteras
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). 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.
Inactivation by uridine diphosphate glucuronosyltransferases
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
De-conjugation by β-glucuronidases
The intestinal bacteria produced β-glucuronidases that de-conjugate SN-38G to SN-38 resulting in entero-hepatic re-circulation of SN-38.
Metabolism by cytochrome P450 enzymes
Irinotecan is metabolized by intrahepatic cytochrome P450 enzymes, CYP3A4 and CYP3A5 into inactive metabolites APC (7-ethyl-10- -N-(5-aminopentanoic acid)-1-piperidinocarbonyloxycamptothecin) and NPC (7-ethyl-10- -amino-1-piperidinocarbonyloxycamptothecin). 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.
Transport to bile
Irinotecan is transported to bile by the ATP-binding cassette (ABC) transporter proteins: ABCB1, ABCC1, ABCC2, and ABCG2.
Elimination
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 to18 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.
Pharmacogenomics
Irinotecan is converted by an enzyme into its active metabolite SN-38, which is in turn inactivated by the enzyme UGT1A1 by glucuronidation.
*28 variant patients
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
Gilbert syndrome (GS) is a syndrome in which the liver of affected individuals processes bilirubin more slowly than the majority. Many people never have symptoms. Occasionally jaundice (a slight yellowish color of the skin or whites of the eyes) ...
. 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.
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.
Approval
Irinotecan received accelerated approval from the U.S. Food and Drug Administration (FDA) in 1996, and full approval in 1998.
Names
During development, it was known as CPT-11.
Formulations
A liposome encapsulated version of irinotecan sold as Onivyde by Merrimack Pharmaceuticals
Merrimack Pharmaceuticals is a pharmaceutical company based in Cambridge, Massachusetts, United States. They specialize in developing drugs for the treatment of cancer.
Merrimack's first FDA-approved drug was approved in 2015; Onivyde, a liposo ...
, was approved by FDA in October 2015, to treat metastatic pancreatic cancer. It was approved for medical use in the European Union in October 2016.
See also
* Etirinotecan pegol, an experimental derivative of irinotecan with a longer half-life in the human body
References
Further reading
*
External links
*
*
Irinotecan Pathway on PharmGKB
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