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Drugs development: more accelerated process
- Conditional approval: Shorter development (only 1 RCTs phase II is required) and review time
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End-point of RCTs:
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MOSTLY Progression-free survival: time interval between relapse
- Chosen by companies as the end-point of the most recent RCTs.
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Overall survival: months gained from treatment to death.
- Focuses more on the patient, Longer follow-up
- They are subjected to PAES/PASS studies: post-marketing surveillance
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Treatment (notes)
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Therapeutic drug monitoring can be used to obtain info of anti-cancer drugs plasma concentration during therapy--> toxicity measurement
- high cost, performed on few drugs, not always necessary
- Genomic sequencing of the patient --> presence of certain mutations --> adequate treatment with controlled PD and PK
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Features of oncological agents
- Narrow(-est) therapeutic index
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They all share a certain degree of TOXICITY
- Cardiovascular toxicity: arrhythmias and QT prolongation by anti-emetic drugs, heart failure , thrombo-embolism (tamoxifen), general risk of ischemia and TdP
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DRUG INTERACTION (primary relevance)
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With NON anti-cancer drugs: antiemetic, analgesic, anticoagulants, anti-depressants, fatigue-treating drugs will be administered too.
- ANTI-DEPRESSANTS: Frequently prescribed (psychiatrist). E.g . St. John's wort widely used by cancer patients: lowers anti-cancer drugs effects.
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ANTI-EMETICS: they are added (one or more) to the chemotherapy therapy according to the patient's risk (CINV)
- MAIN CLASSES: They differ in half-life
- CLASSIFICATION of CINV: Acute (5-6h), delayed (days 2-5), breakthrough, anticipatory, refractory
- ACUTE: It's related to serotonin release (in the gut: peripheral pathway) --> it's managed by blocking serotonin receptors (Ondansetron)
- DELAYED: It's related to substance P release (medulla: central pathway) --> Nk1 receptor antagonist is prescribed (Aprepitant)
- Breakthrough: CINV occurs despite prophylaxis --> implement new anti-emetic
- Anticipatory: CINV occurs before treatment --> strongly influenced by anxiety --> benzodiazepines
- Refractory: CINV occurs in the subsequent cycles
- If the conditions are co-existent, different concomitant drugs will be prescribed or specific combinations containing both active principles (e.g.: NEPA)
- CLASSIFICATION of emetogenic potential of anti-cancer drugs
- HIGH (>90% of patients): Cisplatin, cyclophosphamide
- 3/4 drugs regimen: serotonin receptor antagonist + NK1 antagonist + dexamethasone + olanzapine
- MODERATE: MOST of drugs: cyclophosphamide (low doses), doxorubicin, irinotecan, oxaliplatin, ribociclib
- Dual therapy
- LOW: Fluorouracil, Liposomal doxorubicin, cetuximab, trastuzumab-entasine, osimertinib, entrectinib
- MINIMAL: Atezolizumab, trastuzumab, CPI class
- Anti-dopaminergic drugs are used
- METOCLOPRAMIDE (PLASIL): blocks type 2 dopamine receptor, type 3 and 4 serotonin receptors --> more effective but able to enter BBB (side effects in pyramidal pathways)
- DOMPERIDONE: blocks type 2 dopamine receptors only --> safer but also acts on the heart channels --> QT prolongation
- RISK FACTORS: age, female sex, PMH of nausea, chosen drug side effects
- With ANTI-CANCER drugs: to increase efficacy, decrease resistance development and side effects (toxicity)
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Classification
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CONVENTIONAL CHEMOTHERAPY: CYTOTOXIC DRUGS (hematological and solid tumours)
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Cytotoxic, genotoxic and mutagenic properties
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Mainly target cellular pathways, altering transcription and synthesis of cancer genes, hampering immune response
- Cell-cycle specific (CCS): target only PROLIFERATING CELLS inhibiting S phase, non-SELECTIVE
- Not very effective in slow proliferative cancer cells (colorectal cancer)
- Side effects targeting other proliferating sites (intestinal mucosa, hair)
- Cell-cycle non specific (CCNS): target both PROLIFERATING and NON-PROLIFERATING CELLS, in all cell cycle phases.
- Can be combined in treatment
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FEATURES
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LOG-KILL hypothesis
- Given dose of chemotherapy kills the same fraction of tumour cells regardless of the size of the tumour at the time of treatment.
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Administered in cycles --> To hamper resistance/toxicity developed through the therapy
- Also to allow healthy cells recovery
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DRUG RESISTANCE types: pre-target, on-target, post-target.
- P-GLYCOPROTEIN mechanism: mediates absorption, metabolism and elimination in SEVERAL tissues --> changes plasma concentration
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DRUG TOXICITY (PD): dose-dependent, time-dependent, patient-dependent; also could be unpredictable.
- Grading system of toxicity: ranges from 1-5 (section 4.2, 4.4, 4.8 of SPC)
- Can lead to therapy suspension, hospitalization, medical intervention
- Temporal classification
- Immediate onset: within 2 days: mostly vomiting
- Early onset (1-2 weeks): myelosuppression
- Delayed onset (within months, years): usually irreversible
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TYPES:
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1. Alkylating agents:
- Cyclophospamide (her2 positive breast cancer): IV and oral administration, induces myelosuppression --> granulocytes count for dose adjustment, immunosuppressive drug
- Metabolised by hepatic cytochromes --> one pathway can induce acrolein production --> urothelial toxicity (hemorrhagic cystitis: SPECIFIC SIDE EFFECT)
- Can be co-administered with MESNA: displaces acrolein
- Posology varies significantly depending on the patient
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2. Platinum combination complexes:
- Oxaliplatin (metastatic colorectal cancer): controlled IV injection (3-4h), more tolerated
- More selective for low proliferating cells, lower toxicity but peripheral neurotoxicity , mild myelosuppressor, renal impairments
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3. Antimetabolites: endogenous metabolites antagonists.
- 3 classes: folic acid analogues (Methotrexate), pyrimidine analogues, PARP inhibitors
- Pyrimidine analogues: FLUOROURACIL (5-FU) DNA synthesis inhibition in GI tract cancers (in folfiri ... regimens)
- Synergistic effects: with folinic acid, oxaliplatin
- 80% undergoes catabolic pathway: if DPD is missing --> accumulation --> toxicity
- Side effects: Hand-foot syndrome, no co-administration with brivudine
- Drug interaction: no co-administration with brivudine, DPD congenital deficiency.
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4, Antimitotics
- 1. TAXANES : microtubules stabilization --> mitosis is blocked (CCS)
- PACLITAXEL: IV administration for different cancers, metabolised by liver
- Can induced hypersensitivity --> pre-medication with anti-histamine, corticoids is recommended
- Side effects: myelosuppressor, neurotoxicity (peripheral).
- 2.TOPOISOMERASE INHIBITORS: class I and II
- CLASS I: IRINOTECAN: (large intestine cancers) metabolised into SN-38
- It is transformed into SN-38G by UGT1A1: if deficient --> toxic for GI tract mucosa --> diarrhea (Loperamide)
- CLASS II: Anthracyclines associated with early or delayed cardiotoxicity
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TARGETED THERAPY: inhibition of specific ONCOGENES and receptors --> more selective and effective (cytostatic and cytotoxic)
- SYNTHETIC LETHALITY approach: targets are growth factors (overly-expressed), INC kinases, angiogenesis mediators, immune system
-
2 FAMILIES:
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TKI: TYROSINE KINASE inhibitors (nibs)
- TARGETS:: RAF kinase, MEK, CDK 4/6 (Ribociclib), PI3K pathway, multikinase inhibitors
- Relevant: toxicity of CDK 4/6 inhibitors: neutropenia, diarrhea, thrombosis, interstitial lung disease, QT prolongation, skin toxicity
- e.g. EGFR inhibitor: osimertinib
- Oral administration (home treatment)
- Hepatic and renal clearance (pharmacokinetic interactions); not necessarily selective (off-target effect)
- Pharmacokinetic drug interactions with PPI --> reduce TKI absorption
Pharmacokinetic drug interactions with cytochrome CYP inhibitors or inducers
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MONOCLONAL Abs (MoAbs): several pharmacodynamic properties such as CDC and ADCC
- e.g. EGFR inhibitor: cetuximab
- Parenteral administration via IV/subcutaneous
- Target-selective and target- specific clearance -->low pharmacokinetic interactions
- Toxicity: hypersensitivity, increased (autoimmunity) or depressed (infections, cancer) immune response
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INNOVATIVE: Antibody-drug conjugates (ADCs)
- e.g Trastuzumab entasine
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IMMUNOTHERAPY: immune system stimulation potentiation --> cancer cells destruction
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CLASSES:
-
IMMUNE CHECKPOINT INHIBITORS (ICI):
- FEATURES
- Dosage is the same for all the patients: FLAT DOSE administered via peripheral IV line (home treatment)
- Delayed response: initially the tumour progresses
- irRECIST criteria have been designed to monitor immune-related response (specifically for immunotherapy)
- Long-lasting survival rate is higher (in terms of PFS or OS?)
- TARGETS: CTL4 , PD1 (both on T cells) and PD-L1 on tumour cells
- Mechanism of action in cancer cells: PD-L1 over-expressed on tumour cells--> inhibits T cell response
- PHARMACODYNAMIC: activation of immune cells --> T-cells and APCs kill the tumour cells
- OPPOSITE APPROACH compared to conventional and target chemotherapy
- IMMUNE-RELATED ADVERSE EVENTS (iRAEs) (increased in combination regimens): due to immune system over-stimulation --> arise within 4-10 weeks --> efficacy markers
- It can affect ALL the organs and yield MULTISYSTEM iRAEs, varies according to the drug --> corticosteroids for management
- Rare cardiotoxicity --> myocarditis with high fatality rate
- Drugs in clinical use:
- General comparison between therapy types
-
Trials
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Umbrella trials: different drugs are tested to target different mutations of the same cancer
- E.g. lung cancer high heterogeneity
-
Basket trials: the same drug (tissue-agnostic class) is used to target the mutation shared by different cancers
- E.g. pembrolizumab used in all metastatic or unresectable (...) solid tumours