Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products: 

  • Topoisomerase Inhibitors: Irinotecan

    • Irinotecan (Campto)

     

    • Overview:

      • 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 

        • 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

          • Wainber ZA Bekaii-Saab T Boland PM Dayyani F Marcarulla T Mody K Belanger B Maxwell F Moore Y Thiagalingam A Wang T Zhang B Dean A First-line liposomal irinotecan with oxaliplatin, 5-fluorouracil and leucovorin (NALIRIFOX) in pancreatic ductal adenocarcinoma:  A phase I/II study European Journal of Cancer (EJC) 151 p14-24 July 2021. ( https://www.ejcancer.com/article/S0959-8049(21)00195-7/fulltext)¹⁴

      • 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

          • Gastric cancer

          • Cervical cancer

          • Anaplastic gliomas

          • Glioblastomas

          • Non-small cell lung cancer.⁷

        • "Oncology Pharmacogenomics I:  Solid Tumors 2010"⁹

          Attribution: Valgus JM Oncology Pharmacogenomics I:  Solid Tumors 2010 https://www.youtube.com/watch?v=MARUoYe3IHE (published 7/2016) Begins with Irinotecan-based case study PharmGenEd Youtube Channel:  https://www.youtube.com/channel/UC_TWgttb1rinhsViBUD_olQ/videos

    • Absorption, Distribution, Pharmacokinetics  Metabolism,  Excretion:

      • 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)

            • Age

            • Sex

            • Use of other drugs concurrently

            • Malnutrition

            • 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

      • Pharmacokinetics:

        • 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

                 

            • Conversion of Irinotecan to its Active Form, SN-38 and Subsequent Inactivation by Phase II Metabolism¹⁰

              Attribution:  Kahn KK Solff JJ Kolesar JM Am J Health Syst pharm 63(22):  2211-2217, 2006. https://www.medscape.com/viewarticle/548037_2 Adapted from Fig 1 of reference 10.

               

            • Irinotecan Metabolism¹¹ 

              Attribution: Adapted from: Yalcin S Role of Pharmcogenics in Gastrointestinaol Cancer, Clinical Applications of Pharmacogenetics, March 2012. https://www.researchgate.net/publication/221929791_Role_of_Pharmacogenetics_in_Gastrointestinal_Cancer

               

            • 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

    • Mechanism of Action:

      • 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

          • Replication

          • Repair

          • Transcription.

        • 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

       

    • Adverse Effects:⁷

      • 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 

                • Diaphoresis

                • Hypersalivation

                • Visual accommodation difficulties

                • Rhinorrhea

                • Abdominal cramps

                • Lacrimation

                • 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

    • Drug Resistance:

      • 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 

       

    • Clinical Uses:⁷

      • National Categories of Evidence and Consensus (NCCN)¹²

        Category 1: "Based upon high-level evidence there is uniform NCCN consensus that the intervention is appropriate." Category 2A: "Based upon lower-evidence there is uniform NCCN consensus that the intervention is appropriate." Category 2B: "Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate." Category 3: "Based upon any level of evidence, there is major NCCN disagreement at the intervention is appropriate."

        National Categories of Evidence and Consensus (NCCN) https://www.nccn.org/professionals/physician_gls/categories_of_consensus.aspx

         

      • 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 

        • Ovarian cancer

        • Non-small cell lung cancer

        • Esophageal and gastroesophageal junctional cancer

        • Cervical cancer

        • Gastric cancer

        • Glioblastomas

        • Anaplastic gliomas⁷