Capsule Cancer 14H200a: Mechanism of Action and Pharmacology, September 2024 PDF

Mechanism of action and pharmacology of selected small molecule-based antineoplastic drugs Capsule Cancer 14H200a Patrycja Nowak-Sliwinska 23 September 2024 Objective: Describe the mechanism of action of selected cancer therapies,...

Mechanism of action and pharmacology of selected small molecule-based antineoplastic drugs Capsule Cancer 14H200a Patrycja Nowak-Sliwinska 23 September 2024 Objective: Describe the mechanism of action of selected cancer therapies, their administration, side effects and interaction with other drugs 1  Examples of anti-cancer drugs 3 4 Alkylants cyclophosphamide, cisplatine, bléomycine 2 Antifoliques méthotrexate 1 Antipurine/pyrimidine fluorouracil, capecitabine Inhibiteurs de topoisomérases/agent intercalant irinotécan, doxorubicine Poison du fuseau vincristine, paclitaxel Anticancéreux ciblés imatinib, bortézomib, tamoxifène Immunothérapie nivolumab, imiquimod, CAR T cells Anticancéreux ciblés, anticorps trastuzumab, cetuximab, bevacizumab See also the courses of Prof. C. Samer, Prof. Borchard and Prof. F. Gervasio 2  IRINOTECAN Irinotecan Dilutable solution for infusion, single-dose vials of: 40 mg/2 ml, 100 mg/5 ml, 300 mg/15 ml, 500 mg/25 ml 1000 mg/50 ml of irinotecan hydrochloride (concentration 20 mg/ml) Sterile, clear, light yellow solution See also the course of Prof. C. Samer 3  IRINOTECAN Irinotecan Synthetic campothecin (alkaloid from Camptotheca acuminata) analogue Topoisomerase inhibitors: irinotecan and topotecan They have greater clinical activity and less toxicity than the natural alkaloid Composé synthétique de la campothecine —> inhbiteur de la topoisomerase —> Prdorug transformée en son metablisme actif SN 38 dans le foie. Puis glucoronidé Prodrug activated in liver SN-38, becomes SN- 38G in the liver, and goes into circulation 4 Bailly C, Pharmacol Rev, 2019  IRINOTECAN Mechanism of action Topoisomerase enzymes: maintain the special characteristics of DNA topoisomerase est une enzyme qui peremte de dérouler l’ADN —> L’irinotecan bloque cette activité : interfère avec le mouvement de réplication => arrete la replication irinotecan Binds to topoisomerase I, preventing it from binding DNA Topoisomerase I increased twisting pressure interferes with the moving replication fork, inducing replication arrest and lethal double-stranded breaks in DNA breaks DNA apoptosis or senescence S-phase specific 5  IRINOTECAN Indications (in adults) Switzerland: metastatic colon or rectal carcinoma -1st line: in combination with 5-fluorouracil (FU)+Folinic Acid (FA) or with bevacizumab+5-FU+AF advanced colorectal cancer -2nd line (monotherapy): after failure of prior 5-FU therapy metastatic colorectal cancer (Epidermal growth factor receptor (EGFR)-expressing) who have failed cytotoxic therapy : in combination with cetuximab outside CH (FDA approved): pancreatic cancer Donnée en combinaison pour cancer colorectal —> Beviczumab est une anticorps qui inhibe egfr small cell lung cancer (SCLC) En monotherapie en 2 eme ligne pour cancer colorectal avancé Pour metastases du cancer colorectal chez les personnes surexprimant les egfr www.compendium.ch 6  IRINOTECAN Administration As monotherapy (2nd line treatment): Administration every 3 weeks (elderly patients): 350 mg/m², administered i.v. infusion over 30 to 90 mins par rapport a la surface de la personne et pas de la tumeur Weekly administration (younger patients / patients who may require monitoring): 125 mg/m², administered as a 90-min i.v. infusion once a week for 4 consecutive weeks, followed by 2 weeks without treatment 7  IRINOTECAN Administration (cont) In combination with 5-FU+AF (1st line treatment): Weekly administration: 80 mg/m² of i.v. infusion over 30-90 minutes, followed by AF (500 mg/m², 2 h infusion), then 5-FU (2.3 g/m², 24-h infusion), administered once weekly for 6 weeks, followed by one week without treatment Administration every 2 weeks: On day 1, 180 mg/m² i.v. infusion over 30-90 minutes once every 2 weeks, followed by FA (200 mg/m² as a 2-h infusion) and 5-FU (400 mg/m² bolus followed by 600 mg/m² as a 22-h infusion). On day 2, FA and 5-FU are administered at the same doses and according to the same schedule 8  IRINOTECAN Administration (cont) In combination with cetuximab: Dosing is consistent with that used for monotherapy Cetuximab is administered once weekly as an intravenous infusion; the initial dose is 400 mg/m² over 2 hours, subsequent doses are 250 mg/m² over 1 hour. Irinotecan should be administered no sooner than 1 hour after completion of the cetuximab infusion. 9  IRINOTECAN Pharmacokinetics Absorption T1/2 of irinotecan: 6 to 12 h. T1/2 of the active agent: SN-38: 15 h For the "every 3 weeks" regimen at the recommended dose of 350 mg/m², for the "weekly" regimen at the recommended dose of 125 mg/m² Distribution Plasma protein binding measured in vitro is approximately 65% for irinotecan and approximately 95% for SN-38. 10  IRINOTECAN Pharmacokinetics (cont) Metabolism Hydrolysis by carboxylesterases (CE) (irinotecan to an active metabolite: SN-38); oxidation by CYP3A4 of the terminal piperidine ring - results in pharmacologically-inactive oxidation products, glucuronidation by UGT1A1 of SN-38 yields an inactive metabolite, SN-38 glucuronide (SN-38G). Unchanged irinotecan accounts for the majority of plasma forms, followed SN-38G and SN-38. 3—>processus de métabolisme : hydrolyse, oxydation et glucoronidation Hydrolyse : perte d’une molecule d’eau , catalysé par carboxylesterase => SN38 —> Oxydation par les CYP3A4 —> Glucuronidation du SN-38 qui donne un composé inactif et qui permet son elimination par reins => Aussi elimination par feces Elimination The total body clearance is about 15 l/h/m², the terminal phase half-life is 10 h. More than 50% of the i.v. administered dose is excreted unchanged, of which 33% is excreted in the feces and 22% in the urine. 11  IRINOTECAN Interactions CYP3A4 and/or UGT1A1 inhibitors: may increase systemic exposure to irinotecan or SN-38. Glucuronidation inhibitors: When irinotecan is co-administered with UGT1A1 inhibitors such as atazanavir or erlotinib (atazanavir additionally inhibits CYP3A4), systemic exposure to SN- 38 may be increased. Anticonvulsants (e.g. carbamazepine, phenobarbital, or phenytoin): decrease plasma concentrations of irinotecan and its metabolites SN-38 and SN-38G. Ketoconazole: significant decrease in the AUC of the glutamine metabolite and a marked increase in the AUC of SN-38 compared to a single dose of irinotecan. https://www.swissmedicinfo.ch/default.aspx?Lang=DE 12  IRINOTECAN Contraindications -Chronic inflammatory bowel disease and/or intestinal obstruction -Hypersensitivity to irinotecan -Pregnancy and lactation -Elevated bilirubin levels (hyperbilirubinemia) -Severe bone marrow dysfunction -Dialysis 13  IRINOTECAN Side effects Early/acute diarrhea: This effect occurs due to inhibition of the enzyme acetylcholinesterase, responsible for acetylcholine breakdown (hydrolysis) and promoting excessive cholinergic activity. Irinotecan-induced cholinergic syndrome presents not only as acute diarrhea but also includes diaphoresis, visual accommodation difficulties, or 2 EI principaux : diarrhée (rapide dans les 24h qui suivent le ttt, et les retardée qui arrive jusqu’a 10 jours apres) et myélosuppression abdominal cramps. These symptoms occur within the first 24 hours of irinotecan administration and can be ameliorated with anticholinergic agents. 14  IRINOTECAN Side effects Late/delayed diarrhea: 2-10 days later, cytotoxicity induced by SN-38 that can cause both reduced proliferation (hypoproliferation) in the large and small intestine with damage to the colon and apoptosis. Myelosuppression (bone marrow suppression,15% to 50% of patients): neutropenia is less likely to be observed in patients with reduced frequency drug administration. Fatal result may occur with concurrent presentation of both neutropenia and diarrhea. 15 Flash card IRINOTECAN Class: synthetic campothecin, antineoplastic MoA: inhibitor of topoisomerase I Indications: Metastatic tumors of colon and rectum (in combination with other agents) Side effects: diarrhea and myelosuppression Interactions: CYP3A4 and/or UGT1A1 inhibitors Dosage: 350 mg/m², i.v. infusion over 30-90 mins every 3 weeks 125 mg/m², i.v. infusion over 90 min once a week (younger patients/ patients who may require monitoring) 16  DOXORUBICIN Doxorubicin Doxorubicin is a substrate for the cytochromes P450 CYP3A4 and CYP2D6, as well as P-glycoprotein (P-gp) substrat du 3A4 et 2D6 et de la PgP —> Isolé depuis des especes vivantes (ici une bacterie) —> activité antinéoplastique Isolated from Streptomyces bacterium, doxorubicin is an anthracycline-derivative antibiotic with antineoplastic activity Bailly C, Pharmacol Rev, 2019 17  DOXORUBICIN Pharmaceutical form Solution for injection 2 mg/ml 10 mg/5 ml 50 mg/25 ml 100 mg/50 ml 200 mg/100 ml Trade names: Adriamycin Caelyx (8S-cis)-10-[(3-Amino-2,3,6-trideoxy-alpha-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8- Myocet (hydroxyacetyl)-1-methoxynaphthacene-5,12-dione others hydrochloride 18  DOXORUBICIN Mechanism of action (i) intercalation into DNA and disruption of topoisomerase-II-mediated DNA repair (ii) generation of free radicals and their damage to cellular membranes, DNA and proteins 2 mecanisme d’actions reconnus comme principaux —> Intercale au niveau de l’ADN et perturbe l’activité de topoisomerase —> génère des radicaux libres et casse membrane cellulaire 19  DOXORUBICIN Doxorubicin-targeted cell types son actviité est présente dans differents types de cellules dans le corps —> Peut interagire avec les fibroblastes cardiaques —> Avec cellules endotheliales (vaisseaux sanguins) —> cellules osseuses Cardinale, Front. Cardiovasc. Med., 18 March 2020 | https://doi.org/10.3389/fcvm.2020.00026 => Cellules sensibles et peuvent créer des EI 20  DOXORUBICIN Indications (in adults) Switzerland breast cancer bronchial cancer soft tissue sarcoma and osteosarcoma gynecological and bladder cancer testicular tumor thyroid cancer Ewing's sarcoma nephroblastoma neuroblastoma others 21  DOXORUBICIN Administration plus rapide que irinotecan Slow i.v. injection over 3-10 minutes or, in exceptional cases, by prolonged i.v. infusion over 48-96 hours Monotherapy: 75 mg/m² every 3 weeks Monotherapy in previously treated patients undergoing multidrug therapy: 30-60 mg/m² body surface area every 3 weeks Hematologic diseases: 0.6 mg/kg/day for 3 days or 0.8 mg/kg/day for 2 days, with a treatment-free interval of at least 10 days between the series of injections 22  DOXORUBICIN Pharmacokinetics Absorption: Intravenous administration Distribution: Doxorubicin is distributed with a volume of 700-1100 l/m². Passage into the cerebrospinal fluid is minimal. Doxorubicin distributes rapidly into the ascites, where it reaches concentrations above the plasma level. Plasma protein binding is 50-85%. Metabolism: Doxorubicin is partially metabolized. The main metabolite is active doxorubicinol. Metabolism takes place both in the liver and extrahepatically. Elimination: mainly via the bile and feces, 40-50% as unchanged drug and 23% as doxorubicinol. Renal elimination is minimal. The clearance of doxorubicin is 400-583 ml/min/m², the terminal half-life is 17 h (metabolites 30-50 h). 23  DOXORUBICIN Interactions Inhibitors of CYP3A4, CYP2D6 and/or P-glycoprotein (e.g. verapamil): increased concentration and clinical effects of doxorubicin Inducers of CYP3A4 (e.g. phenobarbital, phenytoin, St. John's Wort) and P-gp: decrease the concentration of doxorubicin Co-administration of ciclosporin and doxorubicin: increase in the concentration of doxorubicin peut augmenter la toxicité d’autres médicaments anti neoblastiques Doxorubicin may enhance the toxicity of other antineoplastic therapies and vice versa 24  DOXORUBICIN Interactions (cont) Trastuzumab: Concurrent use of doxorubicin with trastuzumab results risque augmenté de toxicité cradiaque increased risk of cardiac disfunction. Paclitaxel: given prior doxorubicin, increases the plasma-concentrations of doxorubicin and it’s metabolites. 6-mercoptopurine: doxorubicin may potentiate 6-mercoptopurine-induced hepatotoxicity. 25  DOXORUBICIN Contraindications Hypersensitivity to doxorubicin, other anthracyclines Pre-existing bone marrow suppression Liver impairment Severe heart failure Recent myocardial infarction Acute myocardial disease of inflammatory origin Severe arrhythmias Pregnancy, lactation 26  DOXORUBICIN Side effects Myelosuppression: leukopenia, neutropenia, anemia, thrombocytopenia Cardiomyopathy: reduction in left ventricular ejection fraction, arrhythmia, tachycardia, myocardial damage Gastrointestinal disorders: mucosal inflammation/stomatitis (70%), vomiting (45%), nausea (12-21%), diarrhea (14%), decreased appetite (29%) myélosuppression, cardiomyopathie, GI, développement d’autres tumeurs malgines (surtout dans le snag) Secondary malignancies: e.g. secondary AML 27  DOXORUBICIN Side effects (cont) Extravasation and tissue necrosis Alopecia (hair loss) Fever Pain swelling at the i.v. site 28 Flash card DOXORUBICIN Class: anthracycline-derivative antibiotic, antineoplastic MoA: Inhibits DNA & RNA synthesis, S-phase specific Forms free radicals that cause strand breakage Indications: multiple solid tumors Side effects: myelosuppression, cardiomyopathy, GI impairment Interactions: CYP3A4 inducers, CYP3A4, CYP2D6, P-glycoprotein inhibitors Dosage: only i.v., 75 mg/m² body surface area every 3 weeks (as monotherapy) 29  BORTEZOMIB Bortezomib Bortezomib: dipeptide boronic acid derivative and Synonims: proteasome inhibitor 179324-69-7 inhibiteur proteasome et casse l’homeostasie des processus qui concernet les prot Velcade PS-341 LDP-341 [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid 30  BORTEZOMIB Proteasome inhibitors 31  BORTEZOMIB Mechanism of action Bortezomib reversibly binds to the chymotrypsin-like subunit of the 26S proteasome, resulting in its inhibition and preventing the degradation of various pro- apoptotic factors. Paramore, A., Frantz, S. Bortezomib. Nat Rev Drug Discov 2, 611–612 (2003) 32  BORTEZOMIB Administration Bortezomib can be administered intravenously or subcutaneously. 1.3 mg/m² twice weekly over a two-week period (minimum 72-hour dosing interval) followed by a 10-day treatment break. Multiple Myeloma - Previously Untreated Patients (in combination with melphalan and prednisone): In addition to bortezomib (as above), oral melphalan (9 mg/m² body surface area) and oral prednisone (60 mg/m² body surface area) are administered on days 1-4 of every other cycle. Other patient groups : see compendium.ch 33  BORTEZOMIB Pharmacokinetics administered intravenously (1 mg/mL) or subcutaneously (2.5 mg/mL) Absorption: After s.c. administration (20.4 ng/ml), the Cmax was lower than after i.v. administration (223 ng/ml). Distribution: Plasma protein binding of bortezomib is 83%. Metabolism: mainly metabolized with the participation of CYP 3A4, 2C19, 1A2 and 2C9. Separation of boron results in the formation of two inactive metabolites that are subsequently hydroxylated. Elimination: 40-193 h, cleared by hepatic metabolism. 34  BORTEZOMIB Indications (Switzerland, in adults) Multiple Myeloma Untreated patients: In combination with melphalan and prednisone Patients with relapsed/refractory multiple myeloma who have received at least one prior therapy: In combination with standard chemotherapy and stem cell transplantation. Mantle cell lymphoma Untreated patients for whom hematopoietic stem cell transplantation is inappropriate: in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone. 35  BORTEZOMIB Interactions CYP3A4 strong inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort): reducing Bortezomib efficacy. CYP3A4 weak inducers (e.g. dexamethasone) did not significantly influence the pharmacokinetics of bortezomib. CYP3A4 inhibitors (e.g. ketoconazole, ritonavir): increasing Bortezomib Efficacy. 36  BORTEZOMIB Side effects GI toxicity: nausea, diarrhea, constipation, vomiting Fatigue Muscle cramping, muscle weakness Myelosuppression: thrombocytopenia, anemia, neutropenia Peripheral neuropathy (including sensory), headache Hypotension Decreased appetite Rash Others 37 Flash card BORTEZOMIB Class: dipeptide boronic acid derivative, antineoplastic MoA: proteasome inhibitor, inhibits nuclear factor (NF)-kappaB damage DNA, cells death, cell cycle S-phase specific Indications: Multiple Myeloma Mantle Cell Lymphoma Side effects: GI toxicity, fatigue, myelosuppression, peripheral neuropathy Interactions: CYP3A4 inducers and inhibitors Dosage: see indication in compendium 38  References Weinberg RA, The Biology of Cancer, II ed Bailly C, Pharmacol Rev, 2019 www.swissmedicinfo.ch www.compendium.ch Cardinale, Front. Cardiovasc. Med., 2020 Paramore, A., Frantz, S. Bortezomib. Nat Rev Drug Discov 2, 611–612 (2003) Groll et al, Structure, 2006, 451-456 39 quiz! 40  Question 1 Which of the drugs below may cause cardiomyopathy? A. Bleomycin B. Prednisone C. Doxorubicin D. Mechlorethamine E. Dacarbazine 41  Question 2 Which of the following statements concerning bortezomib is NOT correct: A. Is approved for treatment of Multiple Myeloma and Mantle Cell lymphoma B. Is a topoisomerase II inhibitor C. Interacts with CYP3A4 inducers and inhibitors D. May cause GI toxicity, fatigue, and/or myelosuppression E. Its plasma protein binding is >80%. 42  Question 3 Which enzyme converts IRINOTECAN to SN38? A. Cathepsin B. Carboxylesterase C. Topoisomerase I D. Topoisomerase II E. Caspase 43  Question 4 A 62-year-old woman with advanced cancer is to begun a chemotherapy with doxorubicin + bleomycin + vinblastine + dacarbazine Which statement best explains the mechanism of anticancer action of doxorubicin? A. Intercalates between DNA strands and inhibits topoisomerase II B. Prevents microtubule disassembly into tubulin monomers C. Prevents assembly of tubulin dimers into microtubules D. Alkylates nucleophilic groups on DNA bases E. Blocks the synthesis of both ribonucleotides and deoxynucleotides 44  Question 5 Type of therapy for cancer patients that is given after surgery to kill microscopic forms of cancer that are invisible to the naked eye is called: A. Chemoprophylaxis B. Combo chemotherapy C. Neoadjuvant therapy D. Targeted therapy E. Adjuvant therapy 45