Medical Pharmacology Chapter 33-34: Anticancer Drugs
Topoisomerase Inhibitors: Irinotecan
Irinotecan (Campto) was approved in the United States in 1996 initially for patients with colorectal cancer (advanced) that had become resistant to 5-fluorouracil (5-FU).8
Currently, irinotecan is FDA approved in treating metastatic colorectal cancer in both first-line treatment (in combination with 5-FU/leukovorin) and in single-agent administration for second-line management of progressive colorectal cancer following 5-FU-centered treatment.7
Irinotecan may also be used in combination with oxaliplatin and 5-FU as first-line treatment for pancreatic cancer.
Additionally, irinotecan combined with cisplatin or carboplatin can be used for small cell lung cancer in addition to:7
Refractory esophageal cancer
Esophagogastric junction cancer
Non-small cell lung cancer.7
Absorption and Overview:
Irinotecan is typically administered by the intravenous (IV) route of administration, either as a single agent or in combination with others, for example bolus 5-FU/leukovorin.8
Standard doses of irinotecan may result in substantial variation in systemic exposure to the drug.
This variability in pharmacokinetic as well as pharmacodynamic characteristics appear due to many factors such as:
Genetic variability (inherited)
Use of other drugs concurrently
Physiological changes induced by the cancer itself
Tumor invasion, and
Abnormal organ system function.8
Another formulation of irinotecan is liposomal irinotecan.
This formulation which may be administered along with 5-fluorouracil and leukovorin is available for managing metastatic pancreatic adenocarcinoma following initial gemcitabine protocols.
Side effects associated with the liposomal formulation include both GI toxicity and myelosuppression.5
Irinotecan plasma levels, following IV infusion, exhibit a multi-exponential decay.8
The terminal irinotecan elimination half-life ranges from about 6 to 12 hours.
However, the half-life of the active agent, SN-38, is considerably longer, averaging about 15 hours.
The long duration of SN-38 is thought to be due to continual transformation of irinotecan to SN-38 by carboxylesterases localized in tissues.
Although irinotecan metabolism to form SN-38 is catalyzed by several enzyme systems, the principal enzyme catalyzed route for clinical irinotecan activation is carboxylesterase 2.8
Hepatic carboxylesterase 2 is localized in the liver microsomal system.
Subsequently, SN-38 is transformed (detoxified) by a phase II mechanism utilizing the enzyme UDP-glucouronosyltransferase 1A1 forming the glucuronide derivative, SN-38-glucuronide.
This metabolite can be found both in bile and plasma of patients receiving irinotecan. UDP-glucouronosyltransferase appears to be the rate determining step four elimination of the active agent SN-38 derived from the prodrug, irinotecan.
The cytochrome P450 liver microsomal metabolizing system also participates in irinotecan metabolism with the CYP3A4 isoform prominently mediating oxidative metabolism that catalyzes formation of inactive oxidative products.8
A number of different UDP-glucuronosyltransferases have been identified as contributing to SN-38 glucuronidation.8
These are UGT1A isoforms with the predominant one being UGT1A1.
Slight differences in the genetic makeup of this enzyme can lead to differing enzymatic activities including perhaps most importantly those that lead to decreased activation.
Elimination: The principal elimination mechanism is hepatic, phase II; however, about 1/3 of administered irinotecan is observed in the urine in the unchanged form over a two day timeframe, following a 90 minute infusion.
Biliary irinotecan secretion, along with secretion of SN-38 NSN-38G, importantly contribute to drug elimination.
A multispecific organic anion transporter has been identified as likely mediating biliary secretion of irinotecan and related forms of the carboxylate and lactone derivatives.8
The mechanism of irinotecan action follows from its effects on topoisomerase I enzyme function.1
Topoisomerase classes (I and II) act by promoting DNA strand breakage with subsequent resealing.
DNA topoisomerases modulate internal stress in supercoiled DNA such that particular regions are available for:1
Irinotecan is a camptothecin analog that alter topoisomerase I normal function.1
The camptothecins (irinotecan and topotecan) stabilize the normally unstable transient DNA-topoisomerase I cleavable complex, thus interfering with topoisomerase I normal function.
The specific site of interference is at the religation step, leaving the initial cleavage property of topoisomerase I unaffected.
A consequence of interference with the religation step is that interaction of a DNA replication fork with this affected DNA strand causes a permanent double-stranded DNA break, resulting in cell death.1
Irinotecan and topotecan (campothecins) are classified as S-phase-specific agents since active DNA synthesis is required for drug-induced cytotoxicity.
A clinical consequence is that these cytotoxic agents must be exposed to tumor cells for an extended period of time, ensuring that the camptothecin is present when a given tumor cell is dividing and present at an appropriate therapeutic dose level.1
Two principal and common adverse effects (toxicities) associated with irinotecan administration include gastrointestinal manifestations, principally diarrhea and myelosuppression.7
Irinotecan-associated diarrhea appears to be caused by:
(1) A cholinergic effect which causes abdominal cramping as well as diarrhea and presents within a day of drug administration.
This effect occurs due to inhibition of the enzyme acetylcholinesterase, responsible for acetylcholine breakdown (hydrolysis), inhibition of acetylcholinesterase increases acetylcholine concentration promoting excessive cholinergic activity.
The prodrug, irinotecan, is responsible.
Irinotecan -induced cholinergic syndrome presents not only as acute diarrhea but also includes:1
Visual accommodation difficulties
Asymptomatic bradycardia (rarely).1
(2) Direct cytotoxicity induced by the active, irinotecan metabolite SN-38 induces diarrhea occurring after one day.
SN-38 can cause both reduced proliferation (hypoproliferation) in the large and small intestine with damage to the colon and apoptosis.
Early diarrhea due to acetylcholinesterase inhibition may be managed with the anticholinergic, anti-muscarinic drug, atropine.
Symptoms associated with SN-38 cytotoxicities may be treated with the antidiarrheal loperamide (Imodium) and in more serious presentations a protocol involving loperamide along with diphenoxylate/atropine (Lomotil) and tincture of opium.7
The second most frequently noted irinotecan-related toxicity is myelosuppression.1
About15% to 50% of patients receiving irinotecan infusion every three weeks will experience a significant neutropenia.1
This neutropenia is less likely to be observed in patients with reduced frequency drug administration.
Fatal result may occur with concurrent presentation of both febrile neutropenia (about 3% frequency) and diarrhea.1
One mechanism involved in cellular resistance to anticancer effects for topoisomerase inhibitors is based on mechanisms that decrease cellular drug accumulation.1
For example, topotecan is a substrate for the P-glycoprotein multidrug transporter (P-glycoprotein (ABCB1) which supports efflux of a variety of hydrophobic agents including drugs.
This transporter is described as a 170 kDa (kilodalton) polypeptide and is important in blood-brain barrier function but also restricts intestinal drug uptake.13
Pgp substrates diffuse into the cell membrane because of their lipid-soluble properties and then, encountering the transporte, the drugs are translocated back into the aqueous phase (outside).
The Pgp transporte exhibits a large binding region sufficient to transport several substrate molecules at the same time.
Pgp activity appears dependent on ATP thriough ATP hydrolysis or ATP binding 13
By contrast, irinotecan is not a substrate for this transport system.
Cultured cells lacking carboxylesterase activity exhibit irinotecan resistance; however outside this model system, liver as well as blood cells may possess adequate carboxylesterase activity sufficient to catalyze conversion of irinotecan to the active metabolite SN-38.
As a class, camptothecin resistance could occur also from reduced expression or an abnormality (mutation) in its target, topoisomerase I.1
Metastatic colorectal cancer: Irinotecan (Camptosar) has been FDA approved as first-line treatment in combination of 5-FU/leukovorin; Irinotecan administered as a single agent is considered second-line therapy.7
Pancreatic cancer: Irinotecan (Camptosar) has been FDA approved as first-line treatment in combination with oxaliplatin, 5-FU/leukovorin. Category 2A
Advanced stage small cell lung cancer: Irinotecan (Camptosar) has been FDA approved as first-line treatment in combination with carboplatin or cisplatin. Category 2A
Category 2B designation for treating these malignancies:7
Non-small cell lung cancer
Esophageal and gastroesophageal junctional cancer