Clinical Pharmacology Lillian Siu Role of chemotherapy • Curative therapy – survival • Palliative therapy – quality of life, clinical benefit • Adjuvant therapy –
Download ReportTranscript Clinical Pharmacology Lillian Siu Role of chemotherapy • Curative therapy – survival • Palliative therapy – quality of life, clinical benefit • Adjuvant therapy –
Clinical Pharmacology Lillian Siu Role of chemotherapy • Curative therapy – survival • Palliative therapy – quality of life, clinical benefit • Adjuvant therapy – Neoadjuvant: downstaging – Adjuvant: eradication of micrometastases – Concurrent: radiosensitization • Disease stabilization – new agents may lead to stability • Chemoprevention Goals of therapy #1. Cure the patient Established cancers reliably cured by chemotherapy – Testicular Cancer – Lymphoma – Choriocarcinoma – Pediatric tumors Goals of therapy #2. Control the cancer Cancers reliably shrunk by chemotherapy (>50%) – Small cell lung cancer – Ovarian cancer – Leukemia – Nasopharyngeal cancer – Hormonal therapy of prostate cancer Goals of therapy #2. Control the cancer Cancers sometimes shrunk by chemotherapy (30-50% responses) – Non-small cell lung cancer – Bladder cancer – Breast cancer – Colorectal cancer – Stomach cancer – Head and neck cancer – Hormonal treatment of breast cancer Goals of therapy #2. Control the cancer Cancers occasionally shrunk by chemotherapy (5-20% responses) – Pancreatic cancer – Prostate cancer – Cervical cancer Goals of therapy #2. Control the cancer Cancers almost never shrunk by chemotherapy(<5% responses) –Kidney cancer –Liver cancer –Thyroid cancer Palliative effects of chemotherapy Chemotherapy may shrink the tumor, provide relief of symptoms and lead to improvement Chemotherapy may cause toxicity which leads to deterioration Benefits of tumor growth delay improvement Toxicity of therapy deterioration Pharmacology • Pharmacokinetics – “what the body does to the drug”….. – absorption, distribution, metabolism and excretion • Pharmacodynamics – “what the drug does to the body”…. – e.g. nadir counts, non-hem toxicity, molecular correlates • Pharmacogenetics – genetic differences in enzymatic metabolism or receptor expression affecting patient outcome Pharmacokinetics • Absorption – Bioavailability: proportion of orally administered drug delivered into circulation. if poor absorption (e.g. gut problem) or high first-pass metabolism – Usually determined by measuring AUC after oral vs iv adminstration Conc Time Pharmacokinetics • Distribution dose – Concentration = ________________ volume of distribution – Distribution determined by: • blood flow to tissues, permeability of tissue membranes to drug • protein binding to plasma proteins and tissue components • fat solubility – Compartments: central (eg plasma), peripheral Pharmacokinetics • Metabolism – Most common site is liver – Phase I (oxidative/reductive) reactions: • eg Cytochrome P450 system cyclophosphamide, VP-16, vinca alkaloids • eg Carboxylesterases - irinotecan • eg DPD - 5-FU • eg Cytosine deaminae - Ara-C – Phase II (conjugative) reactions: • eg Glucuronidation - SN-38, epirubicin • eg N-acetylation; methyltransferases Pharmacokinetics • Excretion – 2 major routes: renal and biliary – Clearance: rate of elimination of drug from the body = dose AUC – Half-life: time required for drug concentration in plasma to by half • alpha -rate of distribution into tissues • beta - rate of elimination from body • gamma - in case of slow, delayed elimination Pharmacodynamics Pharmacodynamic effects: e.g. Toxicity, Response (clinical, biological, molecular) Pharmacokinetic endpoints: e.g. Dose, AUC, Css (steady-state concentration), Time above a threshold concentration Pharmacogenetics • Differences in drug-metabolizing enzymes: – e.g. DPD (dihydropyrimidine dehydrogenase) in 5-FU metabolism – e.g. Cytochrome P-450 enzymes e.g. CYP3A4: cyclophosphamide (activation); paclitaxel (inactivation) • Differences in receptor expression: – Less common Conventional Chemotherapeutics Drug Class Mechanism(s) of Action Examples Alkylating agents Alkylation of DNA (generate +ve charge intermediates which bind to “nucleophilic” groups Mustards Nitrosoureas Antimetabolites Nucleoside (purines, pyrimidines) analogues Antifolates (reduced folates) Inhibition of critical enzymes necessary for DNA synthesis TS inhibitors Cytidine analogues MTX Topoisomerase Formation of “cleavable complex” Camptoinhibitors thecins with topoisomerase + DNA, ultimately leading to DNA breaks Epidodophyllotoxins Anthracyclines Conventional Chemotherapeutics Drug Class Mechanism(s) of Action Antimicrotubule Disruption/Stabilization of mitotic agents spindle Pro-apoptotic (taxanes) Examples Vinca alkaloids Taxanes Platinum compounds Act like alkylators, produce interstrand cross-links and intrastrand adducts Cisplatin Carboplatin Oxaliplatin Antitumor antibiotics Many are topoisomerase inhibitors DNA intercalation Generation of oxygen radicals Bleomycin: causes DNA DSbreaks through binding of Bleoferrous iron complex to DNA Anthracyclines Bleomycin Combination Chemotherapy • Rationale: – minimize resistance – maximize synergy/additivity – avoid drugs of overlapping toxicity – cytokinetic considerations – biochemical considerations Combination Chemotherapy • Rationale: – biochemical considerations: • addition of an agent to overcome drug resistance (eg MDR inhibitor & vinca alkaloid) • cooperative inhibition (eg leucovorin & 5FU) • inhibition of drug breakdown (eg DPD inhibitor & 5FU) • rescue host from toxic effects of drug (eg leucovorin following high-dose methotrexate) Mechanisms of Drug Resistance • uptake into cells: – eg methotrexate • efflux out of cells: – eg vinca alkaloids; taxanes; anthracyclines • drug activation: – eg many antimetabolites • drug catabolism: – eg many antimetabolites • or in target enzyme level: – eg methotrexate (DHFR); 5FU (TS); topoisomerase inhibitors Mechanisms of Drug Resistance • alterations in target enzyme: – eg methotrexate; topoisomerase inhibitors • inactivation by binding to sulfhydryls eg GSH: – eg alkylating agents; cisplatin; anthracyclines • DNA repair: – eg alkylating agents; cisplatin; anthracyclines; etoposide • ability to undergo apoptosis: – eg alkylating agents; cisplatin; anthracyclines; etoposide Stages of New Drug Development Drug Discovery Preclinical Evaluation (In vitro/in vivo testing; toxicity; pharmacology; formulation) Phase I (dose and toxicity finding) Phase II (efficacy testing) Phase III (comparative) Phase IV (post marketing) Drug Discovery • Strategies of new anticancer drug discovery: – Serendipitous observation – Mass screening – Analogue development – Targeted drug synthesis Phase I Clinical Trials • First attempt at evaluating a novel drug or a novel combination of existent drugs in humans (volunteers or patients) • Objectives: – Determine maximum tolerated dose (MTD) [= recommended phase II dose (RPTD)] – Define toxicity profile – Pharmacological evaluation – Biological Correlation – Collect preliminary evidence on antitumor activity Phase II Clinical Trials • Primary endpoints: “Response”: tumor shrinkage, marker reduction If tumor shrinkage is difficult to assess or not expected (ie tumor stabilization is more likely), then % of survival at n months, time-toprogression, etc. may be more relevant – Time-defined endpoints (eg TTP) may be difficult to apply because of lack of comparators Surrogate endpoints that have not been externally validated are unacceptable as primary endpoint Phase III Clinical Trials • Design and analysis: – Controls: historical vs randomized controls – Sample size: is the postulated difference between experimental and control arms realistic? – Intention-to-treat principle: are all pts accounted for? – Endpoints: survival (median, overall, progression-free), QoL – Internal validity and external validity cetuximab trastuzumab EGFR HER-2 bevacizumab VEGFR PDGFR Cell membrane PF-00562271 FAK dasatinib AZD0530 erlotinib gefinitib SRC lapatinib sorafenib lonafarnib bosutinib RAS Nucleus Farnesyl transferase PI3K fRAS perifosine Cyclindependent kinases AKT RAF temsirolimus RAD001 AP23573 mTOR PHA-739358 MK-0457 MP 529 MLN 8054 AZD 1152 MEK ERK midostaurin enzastaurin Protein kinase C PROLIFERATION 26S proteasome flavopiridol seliciclib UCN-01 BMS-387082 vorinostat Histone deacetylases Aurora kinases A, B, C Bl 2356 HMN-214 PXD101 LBH589 FR901228 MS-275 Pololike kinases bortezomib MIGRATION METASTASES ANGIOGENESIS