Drug Safety Pharmacosurveillance: The Future is Now & Spelled G-e-n-o-m-I-c-s Dr. Bruce Carleton University of British Columbia Children s and Women s Health Centre of BC Child & Family Research Institute, Vancouver
Individual variability in drug response can have serious consequences Stevens-Johnson Syndrome (SJS) Adverse Drug Reaction
No one size fits all
WE CAN T TREAT CHILDREN LIKE ADULTS Increased Risk of Severe ADRs in Children >75% of approved drugs used in children are untested in pediatric populations Young children cannot evaluate or express their own response to medications Pediatric dosage forms not available Children metabolize drugs differently than adults
Variability in Drug Metabolites in Childhood Despite Administration of Equivalent Doses e.g. Valproic Acid Increased CYP2A6, CYP2C9 activity in children Increased formation of hepatotoxic metabolite in children
Developmental Modulation of Drug Metabolism in Children eg. Dextromethorphan (cough suppressant) % Metabolite Recovery 100% 80% 60% 40% 20% 0% 1 mo. 6 mo. CYP3A CYP2D6 1 yr 1 to 18 years? 2 3 6 8 10 12 14 16 18 Age (years) adult 20 Leeder et al Drug Metab Rev 2000; 32(S2):281 Metabolized by CYP3A and CYP2D6 Relative contribution of CYP2D6 and CYP3A pathways changes during development Other CYP2D6 substrates: Codeine Acetaminophen Paxil
ADR Surveillance
Who Reports ADRs to Federal Regulators? Manufacturers ~190,000 Health Professionals and Consumers Physicians (700,000 in U.S.) Pharmacists (190,000 in U.S.) 13,825 100% 2,083 15% 7,406 54% FDA 1997
How Big is the Problem of ADR Underreporting? It is estimated that 95% of ADRs are never reported Retrospective review of Toxic Epidermal Necrolysis cases in Canadian burn treatment centres from Jan 1995- Dec 2000. Only 25/674 (4%) of TEN cases were reported to CADRMP (Health Canada)
Passive Surveillance Increased reporting will improve understanding How much increase can reasonably be expected? What is the quality of the reports Are they missing critical data? Modification unlikely to achieve meaningful practice change in the prevention of serious ADRs
Active Surveillance ADR Surveillance clinicians who are trained in ADR recognition, evaluation and reporting Aim is to have full reporting All reports containing as much critical data as possible More standardized and thorough data collection processes
GATC: Genotypic Adjustment of Therapies in Childhood Project Leaders: Bruce Carleton & Michael Hayden
The GATC Project Hypothesis Genetic polymorphisms in drug biotransformation genes underlie a significant portion of concentration-dependent ADRs in children. Goal To develop genotype-based dosing guidelines to predict safety and avoid severe ADRs in children.
GATC Established Active ADR Surveillance Network at 8 sites across Canada Initiated DNA sample collection from ADR cases & controls Operational in 8 of Canada s major children s hospitals Serving 75% of all Canadian children Established community-based ADR Surveillance with the Canadian Pediatric Surveillance Program () Network of 2,300 pediatricians across Canada Funded by Health Canada Began ADR surveillance January 1, 2004 GATC VANCOUVER Children s &Women s Health Centre of B.C. Aug. 2005 Surveillance Initiated GATC CALGARY Alberta Children s Hospital Feb. 2006 Surveillance Initiated GATC WINNIPEG Winnipeg Children s Hospital Feb. 2006 Surveillance Initiated LONDON Children s Hospital of Western Ontario Feb. 2006 Surveillance Initiated GATC GATC GATC GATC TORONTO The Hospital for Sick Children Feb. 2006 Surveillance Initiated OTTAWA Children s Hospital of Eastern Ontario Oct. 2006 Surveillance Initiated GATC MONTREAL Sainte- Justine Children s Hospital Mar. 2006 Surveillance Initiated HALIFAX IWK Grace Health Centre May 2006 Surveillance Initiated
GATC C17 Established Active ADR Surveillance Network at 8 sites across Canada Established community-based ADR Surveillance with the Canadian Pediatric Surveillance Program () Established a collaboration with the Canadian C-17 Oncology Network Network of all pediatric oncology departments across Canada C17 GATC C17 VANCOUVER Children s &Women s Health Centre of B.C. Aug. 2005 Surveillance Initiated C17 GATC C17 CALGARY Alberta Children s Hospital Feb. 2006 Surveillance Initiated C17 REGINA C17 GATC WINNIPEG Winnipeg Children s Hospital Feb. 2006 Surveillance Initiated C17 LONDON C17 Children s Hospital of Western Ontario Feb. 2006 Surveillance Initiated GATC C17 C17 GATC C17 GATC C17 GATC C17 TORONTO The Hospital for Sick Children Feb. 2006 Surveillance Initiated OTTAWA Children s Hospital of Eastern Ontario Oct. 2006 Surveillance Initiated GATC C17 MONTREAL Sainte- Justine Children s Hospital Mar. 2006 Surveillance Initiated HALIFAX IWK Grace Health Centre May 2006 Surveillance Initiated
GATC Clinical Surveillance Network Identify children with ADRs Identify matched children on same medications, without ADRs Look for genetic variation in key drug ADME enzymes Informs new-drug development Develop new dosing guidelines Bedside-benchtop-bedside science
GATC GATC ADR Surveillance- Sample Collection Surveillance sites within hospitals/centres Inpatient wards Outpatient clinics Emergency departments Whenever possible, DNA samples is collected from biological parents of ADR patients
Established ADR Surveillance Networks across Canada Recruited over 8000 ADR cases and drugmatched controls Drug-Matched Controls Severe ADR Cases
the GATC network represents a unique contribution to the world serves as a model for studies worldwide. Arthur Holden, CEO, Serious Adverse Events Consortium (SAEC) The unique opportunities for ADR surveillance in Canada s national healthcare system have been seized upon with the GATC project. Giacomini et al, Nature, 2007 When good drugs go bad
GATC Genomic Analyses
Developed and tested ADME-tox SNP panel ADME-tox SNP Panel Raw Data (n = 480) Classification Genes AA AA Phase I Metabolism Phase II Metabolism Receptors/Drug Targets Transporters Transcription factors Ion Channels 36 41 70 20 19 8 AA AB AB BB AA AB BB AB Call Rates >99% Reprod. 99.99% Others 44 Total (3072 SNPs) 248 BB BB Running Whole Genome analyses when appropriate
Prioritized Focus on Three Serious ADRs: 1. Cisplatin-induced deafness 2. Anthracycline-induced cardiotoxicity 3. Codeine-induced infant mortality
Cisplatin Drug of choice for solid tumours including hepatoblastoma, ovarian, CNS, osteosarcoma, neuroblastoma, lung, bladder, head and neck tumors Commercialization assessment revealed 1,000,000 patients receive each year (N. America & Europe) Cisplatin-Induced Deafness ADR Causes permanent hearing loss 10-38% of patients Increased frequency and severity in children 28% of children 5-14 develop severe hearing loss 38% of children <5 yrs old develop severe hearing loss (Li et al, 2004) B.C. Children s Hospital: 37% of patients developed grade 3-4 deafness since 2005
Cisplatin-ADR Patient Recruitment Target : 150 cases, 150 controls Current: 75 cases, 79 controls Classification of Cisplatin ADR Cases and Controls Controls No hearing loss ADR Cases Grade 3 Hearing Loss: Severe Hearing Loss Requires intervention with hearing aid >20dB hearing loss at 2000 Hz Grade 4 Hearing Loss: Deafness Requires intervention with cochlear implant >40dB hearing loss at 1000Hz
Anthracyclines Administered to 60% all childhood cancer patients Adjuvant chemotherapy in breast cancer (50-90%, 22,000 patients/year in Canada) Commercialization assessment revealed 970,000 patients receive each year (N. America) Anthracycline-Induced Cardiotoxicity ADR Causes severe cardiotoxicity requiring ventricular assist device or heart transplant 10-30% of patients affected B.C. Children s Hospital: 17.9% develop cardiotoxicity (since 2006) Increased severity in children <15yr, esp. <4yr 8% of children end up on cardiac transplant list (BC Children s, 2008) Mortality rate: 61% (BC Cancer, 2005)
Anthracycline-ADR Patient Recruitment Target : 100 cases, 400 controls (July 15, 2008) Current: 78 cases, 313 drug-matched controls Classification of Anthracycline ADR Cases and Controls Controls No cardiotoxicity, shortening fraction >30% ADR Cases Grade 1 toxicity: Shortening fraction 24-30% or Resting ejection fraction 50-60% Grade 2 toxicity: Shortening fraction 15-24% or Resting ejection fraction 40-50% Grade 3 toxicity: Congestive heart failure Shortening fraction < 15% or Resting ejection fraction < 40% Grade 4 toxicity - Congestive heart failure requiring heart transplant or ventricular assist device Resting ejection fraction < 20%
Codeine-Induced Infant Mortality Initial Case Report: A new mother was given a standard dose of Tylenol #3 for obstetric pain relief Complained of significant drowsiness and constipation; dose reduced by 50% Infant showed poor feeding Infant died on day 13 due to respiratory failure Follow-up Analysis: Coroner brings case to GATC Maternal milk contained 87 ng/ml of morphine (10-20x expected) Infant s blood contained lethal levels of morphine (70 ng/ml)
Identified genetic variants associated with lethal reaction to codeine in newborns Mother s Genotype: CYP2D6 gene duplication UGT2B7*2/*2 Opioid activity in brain Outcome: Accumulation of morphine in breast milk Breast milk fed to infant Accumulation of morphine in infant caused CNS depression, respiratory failure, and death Infants do not express CYP2D6 and UGT2B7 and therefore do not metabolize morphine Codeine CYP3A4 Codeine 6-glucuronide Liver CYP2D6 Morphine UGT1A1 UGT2B7 UGT2B7 Morphine 3-glucuronide Morphine 6-glucuronide Kidney Koren et al, Lancet, 2006
Prior to Our Work The American Academy of Pediatrics and Drugs in Pregnancy in Lactation, the major reference guide to fetal and neonatal risk, list codeine as compatible with breastfeeding Briggs et al., 2005; Pediatrics, 2001
FDA Public Health Advisory Aug. 17, 2007
Estimated 1846 newborn infants are at risk for the codeine ADR each year in Canada (340,000 births, 73% breastfed, 52% mothers receive codeine post-childbirth,1.4% risk genotype) NEWS Codeine can turn toxic in nursing mothers May 11, 2006
GATC GATC GATC Overview DNA collected DNA genotyped Adverse Drug Reaction 1900 SNPs in 200 Candidate genes Integrate clinical & genotype data in association analyses Detailed Clinical Data Collected
II. ADR Biomarker Identification Candidate SNP Analysis Adverse Drug Reaction I. ADR Case Identification Novel Biomarker Discovery ADR Biomarker Validation SNP Genotyping Candidate Gene Sequencing ADR patient Controls Pharmacokinetic & proteomic studies Validated targets added to a lowcost diagnostic DNA chip Goal: Provide the scientific foundation to cost-effectively reduce severe childhood ADRs in Canada. III. ADR Biomarker Validation Pharmacokinetic Functional Validation Discovery of Novel ADR Biomarker Incorporation of validated ADR Biomarkers into Diagnostic Chip & SNP Platform Patient to receive drug X DNA Diagnostics ADR Screen Report Drug X: 10-fold increased risk of reaction Drug Y: 5-fold increased risk Drug Z: 20-fold increased risk
GATC Team Clinical Surveillance: Pharmacogenomics: Pharmacokinetics: Data Management: Health Economics: Bruce Carleton, UBC Gideon Koren, Univ of Toronto Stuart MacLeod, CFRI/UBC Michael Hayden, UBC Michael Phillips, Univ of Montréal Steven Leeder, Univ of Missouri Colin Ross, UBC Michael Rieder, UWO David Freeman, UWO Marie-Pierre Dube, Univ of Montréal Wyeth Wasserman, UBC Deborah Marshall, McMaster Kathryn Phillips, UCSF
What Differentiates Our Work Unique active surveillance network Drug-matched controls The Canadian Advantage National Health Care System Network embedded within the Health Care System Pragmatic value identified by stakeholders C17 Network will play a key role in advancing the safe care of patients Oncologists will significantly impact the care and treatment of patients Patients I support this research I ended up in ICU because of my heart BC Children s Hospital President..clear examples of therapeutic value Director, Emerg. Med., BC Children s:..will improve the safe use of drugs in children and adults with cancer Next: The Canadian Pharmacogenomic Network for Drug Safety