Williams Oncology Study Fin
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Talk give at the Northwest Oncology meeting 2012
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Williams Oncology Study Fin
- 1. Mechanisms of unpredictable toxicities Dominic Williams MRC Centre for Drug Safety Science The University of Liverpool dom@liv.ac.uk
- 2. Overview MRC CDSS strategy for adverse drug reaction (ADR) research Classification of ADRs Role of drug metabolism Focus on Drug-Induced Liver Injury (DILI) Mechanisms Polymorphisms in drug metabolising enzymes Pharmacogenetics in the treatment of cancer Neoadjuvant chemotherapy & DILI
- 3. Centre Strategy for Investigating ADRs DRUG Define structural Characterize Investigation basis of ADR Investigation of the liability of the chemical “Closing the loop” patient on adverse drug reactions Identify Characterize causal patient biochemical phenotype/ variable genotype
- 4. Integrated Mechanistic Drug Safety: Patient SAR Drug SMR Class STR Animal Chemistry Clinical Research Man Bioanalysis Mechanism Outcomes Problem Question Biomarkers In vitro Clinical Samples
- 5. Integrated Mechanistic Drug Safety: Chemical SAR SMR STR In vitro Drug / Chemical Man Chemical Biological Bioanalysis Compound Studies Validation Validation Animal Clinical Validation & Application
- 6. Lessons for the future Inform mechanism and pathogenesis Inform the Medicinal Chemist Inform the Clinician Inform the Regulator Inform the Public – what is feasible Develop biomarkers for integrated patient, in vitro & animal studies
- 7. Classification of Adverse Drug Reactions ON TARGET • Predictable from the known primary or secondary pharmacology of the drug • Exaggeration of the pharmacological effect of the drug • Clear dose-dependent relationship OFF TARGET • These are not predictable from a knowledge of the basic pharmacology of the drug • Exhibit marked inter-individual susceptibility (idiosyncratic) • Complex dose dependence
- 8. Drug Metabolism: Pharmacology Cellular DRUG RESPONSE accumulation Concentration in Phase I/II Plasma Drug Stable Disposition metabolites Metabolism Absorption Excretion Drug plasma level Excretion Pharmacological exposure
- 9. Drug Metabolism: Toxicology Cellular DRUG RESPONSE accumulation Concentrations in organs Phase I/II Drug Stable Disposition metabolites Metabolism Absorption Excretion Drug & metabolites Excretion Pharmacological & Toxicological exposure
- 10. Drugs withdrawn from major markets due to hepatotoxicity Drug: Therapeutic area: - Alpidem* Anxiolytic Aspirin (children) NSAID - - Bendazac* NSAID Benoxaprofen NSAID - O NH 2 - Bromfenac* NSAID HO OH Chlormezanone* Anxiolytic - NH - Dilavelol* Anti-hypertensive Ebrotidine* H2 receptor antagonist - - Fipexide* Stimulant Nefazodone* Anti-depressant - - Nimesulide NSAID Nomifensine Anti-depressant - - Oxyphenisatin Laxative Pemoline* ADHD - - Perhexilene Anti-anginal Temafloxacin* Anti-infective - - Tolcapone* Anti-parkinson’s Tolrestat* Anti-diabetic - - Troglitazone* Anti-diabetic Trovafloxacin* Antibiotic - Ximelagatran- Anti-coagulant - Zimeldine Anti-depressant * Need et al., Nat Genetics 2005
- 11. Drug Disposition: Pharmacological & Toxicological Cellular DRUG accumulation Toxicity Phase I/II/III bioactivation Chemically Stable reactive metabolites metabolites bioinactivation Excretion
- 12. Consequences of bioactivation Cellular DRUG accumulation Toxicity Phase I/II/III bioactivation Inhibition Chemically • heme complex Of reactive • protein alkylation P450s metabolites bioinactivation Excretion
- 13. Consequences of bioactivation Cellular DRUG accumulation Toxicity Carcinogenicity Phase I/II/III bioactivation Chemical Stress Modification of: Chemically Necrosis Stable reactive • nucleic acid metabolites metabolites • enzyme • transporter Apoptosis bioinactivation • signalling protein • receptor • random autologous Excretion protein Hypersensitivity
- 14. Consequences of bioactivation: Toxicophores (structural alerts) Cellular DRUG accumulation Toxicity ?? furan thiophene aliphatic amine Phase I/II/III bioactivation aromatic amine epoxide Chemically quinone Stable quinoneimine reactive metabolites carbocation metabolites acyl halide bioinactivation hydroxylamine allylic alcohol acyl glucuronide Excretion PHARMACOLOGICAL ADVERSE EFFECT EFFECT CHEMICAL STRUCTURE
- 15. Hepatotoxic drugs in man: Withdrawn or with warning label Drugs with black warnings for hepatotoxicity* Drugs withdrawn for hepatotoxicity drug dose (mg/day) reactive products drug date dose reactive acitretin 25-50 no (mg/day) products bosentan 125-250 no cincopher 1930 300 no dacarbazine 140-315 yes iproniazid 1959 25-150 yes dantrolene 300-400 yes pipamazinc 1969 15 no felbamate 1200 yes fenclozic acid 1970 300 yes flutamide 750 yes oxyphenisatin 1973 50 no 2011; 10: 1-15 gemtuzumab 9 mg.m-3 yes (?) nialamide 1974 200 yes isoniazid 300 yes tienilic acid 1980 250-500 yes ketoconazole 200 yes benoxaprofen 1982 300-600 yes naltrexone 50 no nomifensine 1986 125 yes nevirapine 200 yes chlomezanone 1996 600 no tolcapone 300 yes bromfenac 1998 25-50 yes trovafloxacin 100-500 no troglitazone 2000 400 yes valproic acid 1000-2400 Yes (10/14 = 71%) nefazodone 2004 200 yes *Definition: a black box warning is the strongest type of warning that the pemoline 2005 38-110 no FDA can require for a drug and is generally reserved for warning prescribers about adverse drug reactions that can cause serious injury or death. An issue here is the benefit/risk ratio.
- 16. Focus on Drug-Induced Liver Injury SM EC CLEARANCE phospholipidosis DRUG bioaccumulation mitochondria microvesicular steatosis METABOLITE organelle impairment lysosome hepatocyte apoptosis REACTIVE METABOLITE hepatocyte necrosis inhibition of biliary efflux CLEARANCE hypersensitivity Intrahepatic cholestasis immunoallergic toxicity
- 17. DILI – a consequence of multiple steps Drug Patient-specificfactors Drug-specific factors 1. 2. 3. Biological response in 4. Biological response in Chemical Insult in liver Drug absorption & disposition target cell tissue e.g. reactive metabolite- e.g. hepatic uptake e.g. cell toxicity, stress e.g. cytokine release, mediated response immune cell response Screening opportunity Outcome: pre-clinical species vs man Amplification vs Innate & adaptive Protection immunity e.g. stress response Tolerance & adaptation Toxicity
- 18. Clinicopathological presentation of DILI CLEARANCE Acute fatty liver with lactic acidosis Acute hepatic necrosis DRUG Acute liver failure Acute viral hepatitis-like liver injury Autoimmune-like hepatitis DRUG Bland cholestasis + Cholestatic hepatitis METABOLITE Cirrhosis Immuno-allergic hepatitis Nodular regeneration Nonalcoholic fatty liver Sinusoidal obstruction syndrome Vanishing bile duct syndrome Multi-cellular and multifunctional organ Multiple and variable forms of disease Multi step pathologies Tujios and Fontana Nature 2011
- 19. Hepatotoxin Accumulation Mit DNA Energy Depletion Fialuridine OXPHOS ROS Generation Fatty acid synthesis Apoptosis HepatocellularTargets Toxic Consequences hENT1 Steatosis Toxicity Mechanisms Inhibits DNA polymerase-γ of Reactive Independent Oxidative Stress Transporters Metabolites Protein Oxidation Decreases MtDNA Perhexiline Apoptosis Fialuridine Necrosis Disrupts electron transportAplovirac chain Tacrine Mitochondria Steatosis ROS generation Valproic Acid Amiodarone Troglitazone Mitochondrial Dysfunction/Cell Death Accumulation Ritonavir • Physicochemical Rifampin • Biochemical NRTIs eg Stavudine • Transport
- 20. Hepatotoxin Accumulation Mit DNA Energy Depletion Fialuridine OXPHOS ROS Generation Fatty acid synthesis Apoptosis HepatocellularTargets Toxic Consequences Steatosis Toxicity Mechanisms Independent of Reactive Oxidative Stress Transporters Metabolites Protein Oxidation Perhexiline Apoptosis Fialuridine Necrosis Aplovirac Tacrine Mitochondria Steatosis Valproic Acid Amiodarone Troglitazone Accumulation Ritonavir • Physicochemical Rifampin • Biochemical NRTIs eg Stavudine • Transport McKenzie et al, 1995 Lai et al, 2004
- 21. Mechanisms of Drug Induced Liver Injury Hepatic Injury Biological stratification Drug • accumulation • Plasma / liver level • bioactivation • GSH/mercapturate • covalent binding • Protein binding • chemical stress • chemical stress DRUG METABOLITE • mitochondrial dysfunction • glutamate dehydrogenase REACTIVE METABOLITE • apoptosis • cytochrome C • hepatocyte hypertrophy • hepatocyte hyperplasia • ALT, AST, SDH, LDH, GST • hepatocyte integrity • ALP, GT, 5’nucleotidase • hepatobiliary integrity Biology • Bilirubin, bile acids, • innate immune activation • hepatic function • prothrombin, metabolism / • fibrosis secretion
- 22. Variation in Drug Metabolism - Toxicity Cellular DRUG accumulation Toxicity VariationH N Phase I/II/III In drug metabolism Stable Perhexiline & metabolites Genetic Variation In genetics Cytochrome P450 enzyme induction enzyme inhibition Excretion disease Shah et al 1982; Davies et al 2007
- 23. Perhexiline Maleate and CYP2D6 H Indications - prevention of angina pectoris N - prevention of ventricular systoles Toxicity - peripheral neuropathy - hepatotoxicity HO H N Pharmacokinetics: T1/2 Metabolic ratio (%D/%M) - ADR patients 2-6 0.3 ± 0.4 + ADR patients 9-22 2.82 ± 0.4 - related to CYP2D6 phenotype (Singlas et al, 1978; Shah et al, 1982; Cooper et al, 1984)
- 24. Lipidosis Induced by Amphiphilic Cationic Drugs N H PHOSPHOLIPIDS PHOSPHOLIPIDS N N N H H H Extracellular Cytosol pH 7.4 pH 7.2 Lysosome pH 4.5
- 25. Prediction of Variation in Drug Metabolism • Human liver banks • Expression systems • Cell lines • In silico techniques / models • Transgenic animals • Volunteer & Patient studies • Genotype • Phenotype Transfer of knowledge Development of to clinical practice pre-clinical screens
- 26. Drug Safety Science and DILI CLEARANCE 20 / safety pharmacology targets 1st effects 2nd effects 3rd effects Ca2+ Occurrence,DRUG Frequency = f1 + f2 DRUG Chemistry Biology of & Severity of + DNA of drug individual Drug Hepatotoxicity METABOLITE phospholipid specific TARGET proteins BIOMARKERS PHARMACOLOGICAL ADVERSE EFFECT EFFECT Dose CHEMICAL STRUCTURE f (chemistry) f (biology) SPECIES and INDIVIDUAL VARIATION
- 27. Drug Safety Science and DILI Occurrence, Frequency & Severity of Drug Hepatotoxicity = f1 Chemistry of drug + f2 Biology of individual N H Amphiphilic 2D6 genotype / Cation phenotype Rationale for Safe clinical use
- 28. Genetic Polymorphisms known to affect response to anti-cancer drugs Relling & Dervieux, 2001; Nature Reviews Cancer
- 29. Pharmacogenetics in the Treatment of Cancer thiopurine methyl transferase 6-mercaptopurine TPMT inactive metabolites Azathioprine Active Incorporation into DNA thioguanine Anti-leukemic effect nucleotides Myelosuppression 1 in 300 have TPMT deficiency Several polymorphisms including G238C, G460A and A719G TPMT deficiency predicts severe neutropenia following treatment with 6-mercaptopurine or azathioprine Krynetski & Evans, 1998
- 30. Thiopurine Methyl Transferase (TPMT) and Treatment of Childhood Leukaemia Myelotoxicity ↑ Risk of 2o cancer Narrow therapeutic index Therapy ↓ toxicity 1:300 have TPMT deficiency Risk of relapse 0.3% mut/mut 10% wt/mut 90% wt/wt Associated with severe Dose adjustment haemopoietic toxicity 6-Mercaptopurine dosage 500 (mg/m2/week) REDUCTION OF DOSE TO 10% CAN LEAD TO SUCCESSFUL TREATMENT 25 0 WITHOUT TOXICITY 25 m /m w t/m w t/w t Krynetski & Evans, 1998
- 31. Neoadjuvant chemotherapy improves progression free survival Neoadjuvant chemotherapy in colorectal liver metastases: 5-fluorouracil Leucovorin Oxaliplatin } FOLFOX 5-fluorouracil Leucovorin Irinotecan } FOLFIRI EORT study: 9.2% improvement 3 year disease-free survival (FOLFOX) Pre-operative chemotherapy can cause problems Nordlinger, Lancet 2008
- 32. Irinotecan Metabolism & Toxicity Irinotecan (Campostar®) is a topoisomerase-I inhibitor pro-drug widely used for treatment of metastatic and recurrent colorectal cancer The most common dose-limiting adverse effects of irinotecan are neutropenia & diarrhoea UGT normally conjugates to & increases hydrophilicity of bilirubin, drugs & xenobiotics Variations in uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene may help predict which patients develop adverse effects Frequency of the inactive allele varies: African (43%), European (39%) Asian(16%)
- 33. Irinotecan Metabolism N CH2CH3 N O O Irinotecan N Cyp 3A4/5 Oxidised O N Irinotecan O Carboxyl H3CH2C OH O esterase CH2CH3 HO O SN38 N (active) N Anti-tumour O activity H3CH2C OH O UGT 1A1 / 7 / 9 CH2CH3 GLUCURONIDE O O N N O Intestinal SN38 H3CH2C SN38-G -glucuronidase SN38-G OH O (active)
- 34. Irinotecan Metabolism & Toxicity CH2CH3 X HO O N CH2CH3 N UGT 1A1 / 7 / 9 O GLUCURONIDE O O H3CH2C N SN38 OH O Intestinal -glucuronidase N O H3CH2C OH O Detoxification Intestine Diarrhoea Bone Marrow Leukopenia Thrombocytopenia Adverse Reaction Anaemia Other metabolic determinants: Carboxylesterase activity CYP 3A4 inhibition Gut transporters Enzyme activity in tumour
- 35. Systemic chemotherapy causes hepatotoxicity Normal Steatohepatitis (Irinotecan) • 19-79% incidence of sinusiodal injury with oxaliplatin vs 5FU alone • steatosis 30-47% patients treated with 5FU • Irinotecan ~20% incidence of steatohepatitis vs 4.4% • ~15% increase in 90 day mortality with SOS (Oxaliplatin) steatohepatitis
- 36. Chemotherapy-induced liver damage Oxaliplatin Irinotecan Sinusoidal obstruction syndrome causes Steatohepatitis causes an increase in 90 increased operative bleeding but no day operative mortality increase in operative mortality ‘Blue’ liver ‘Yellow’ liver
- 37. Systemic chemotherapy causes hepatotoxicity Steatohepatitis (Irinotecan) Steatosis • Impaired hepatic defence • Enhanced oxidative stress • BMI is an independent risk factor in steatohepatitis
- 38. Systemic chemotherapy causes hepatotoxicity SOS (Oxaliplatin) • Drug kills endothelial cells • Leads to sinusoidal disruption • Activation of hepatic stellate cells • Matrix deposition • Sloughing of erythrocytes & blebbing of cytoplasmic processes
- 39. Conclusions Understanding the complex mechanisms of DILI requires an integrated bioanalytical approach – DMPK, genomics, metabolomics & proteomics Understanding mechanisms of DILI will assist with Identifying biochemical risk factors Developing biomarkers of efficacy & toxicity Using potentially toxic drugs more safely Off-target idiosyncratic drug toxicity cannot be predicted from the chemistry of the drug and/or its metabolite because such reactions are by definition (largely) a function of the biology of the individual. Occurrence, Frequency & Severity of Drug Hepatotoxicity = f1 Chemistry of drug + f2 Biology of individual
Notes de l'éditeur
- Different chemical classesAnd different therapeutic areas
- Major consequence of bioactivation is in fact bioinactivation
- Mjajorr consequence of bioactivation is in fact bioinactivation
- Most common consequence of bioactivation is in fact bioinactivation
- The physiological role of the liver is hepatic clearance.Interference with this process, can itself be a cause of DILIDawson et al quantified the inhibition of BSEP ABCB 11 by 85 pharmaceuticals using taurochalate uptake in inverted plasma membrane vesicles from Sf 21 cells which express these proteins.Overall they found that inhibition of both human BSEP and the rat ortholog (rBsep) correlates with the propensitiyOf numerous pharmaceuticals to cause to cause cholestatic DILI
- What are we trying to predict?
- We believe that neoadjuvant chemotherapy is beneficial for patients undergoing resection of colorectal liver metastases. These data are from the EORTC study, where 364 patients with resectable colorectal hepatic metastases were randomized to six cycles of neoadjuvant FOLFOX, followed by surgery and six further cycles of chemotherapy, or surgery alone. Those who received perioperative chemotherapy and were resected had a 9.2% improvement in 3-year disease-free survival.
- However, there is growing recognition that preoperative systemic chemotherapy can adversely affect normal hepatic parenchyma. Patients who receive systemic oxaliplatin are more likely to develop sinusoidal obstructive syndrome, whilst those treated with Irinotecan are more likely to developed steatosis and steatohepatitis. Sinusoidal obstructive syndrome is associated with increased intraoperative bleeding, but no increase in morbidity and mortality. Steatohepatitis is associated with increased post-operative morbidty, and Vauthey at el demonstrated a strong correlation between steatohepatitis and 90-day mortality after resection.