Pharmacovigilance And Pharmacogenetics Flashcards
What is pharmacovigilacne
- Identification, assessment and subsequent prevention of adverse drug reactions whilst optimising benefits
- Responsibility lies with prescribers, patients and carers (pharma, MHRA..)
- The most common clinical adverse event is a drug reaction
- ~6.5% of hospital admissions in the UK related to an ADR
- Circa £530 million cost
- Don’t want to labour the financial implications but consider the extended clinical significance
What are adrs a result of and what classifies them as serious
• Evidence suggests that the vast majority of ADRs are as a result of well profiled therapeutics where the ADRs are well defined and preventable (7/10)
• Most serious ADRs are of importance to morbidity and mortality (relatively rare – would not reach market)
• Through regulation, data is collected about all ADRs for active medicines
• ONE key focus is to identify those that are classed as serious: Fatal
Life-threatening
Prolonged hospitalisation
Long term disability
Congenital abnormalities
- along with medical judgement
What are adrs
• Unintended and noxious
• Attributable to therapeutic given within the normal recommended
human range
• Differs from and adverse event where causality has not been confirmed
• ADRs are easier to identify and confirm in RCT situation (if big enough)
What are type a reactions
Type A (augmented) reactions generally: Dose-related
Predictable from pharmacology Common
Reversible
Manageable with dose adjustment
Warfarin – bleeding, nitrates – headache, hypoglycaemia – oral antidiabetic agents
What are type b reactions
Type B (bizarre) generally:
Not dose-related
Uncommon
Unpredictable
Serious/irreversible
Indicative that the drug needs to be stopped
Anaphylaxis with penicillin, agranulocytosis with clozapine, thrombocytopenia
• Other sub classifications have been proposed: Chronic, Delayed End of use
Describe risk management with the example of the cocp scare
• Oral contraceptives – late 1960’s through spontaneous ADR reporting COCP increased risk of VTE
dose was reduced (reduced risk of VTE) without compromising efficacy
• When the risk became public - “pill scare” helpfully reported by some media → ↓ in OCs without alternative contraception → ↑ induced abortion
• Further scares identified including MI and breast cancer which again resulted in ↓ OC use
• Pregnancy is much riskier (VTE incidence among others) than use of OCs
• Poor communication of the investigations of 2G and 3G COCP have also influenced PV and how to communicate findings
Describe a study design with rt as an example
• Hormone replacement therapy
• Baseline risk of VTE, cancers and CVD is greater so more feasible to
study clinically
• Observational studies had suggested a reduced risk of CVD including MI and stroke – Pharma promoted this (1980’s and 90’s)
• Woman using HRT may be healthier – confounding factors
• Large randomised trials eventually carried out which showed that
actually there was an increased risk of CVD risk
• Complexity of the risks made and still makes it difficult to communicate (although no serious consequence of stopping HRT abruptly cf. COCP)
How is adr detected
Number of patients required to be 95% (p<0.05) sure of detecting an ADR depends on predicted incidence
Relative risk in context of baseline risk
Baseline risk
Relative risk
S
What is dots
Dose relatedness - toxic, collateral, hyper-susceptibility
Time relatedness - independent vs dependant
Susceptibility - age, gender, etc
• Osteoporosis due to corticosteroids – Collateral, late, age and sex Dosage used in therapeutic range, several months of treatment, females and older people
• Anaphylaxis due to penicillin – hyper-susceptibility, first dose, requires previous sensitisation
Very low, sub therapeutic levels, within minutes of taking first dose
What are the nature and mechanisms of adrs
• Usually mimic disease or syndrome that occur naturally
• Importantly, may have non therapeutic causes (causality)
• Some syndromes causality solely due to therapeutic agents (so far)
Diethylstilboestrol prevent premature labour – vaginal cancer in those exposed in utero
Fibrosing colonopathy – large doses of pancreatic enzymes used in treating children with CF
Whar are moas for. An adr
Broadly four MOA for an ADR Exaggerated response (bleeding warfarin)
Desired pharmacological effect at alternative/additional site (GTN – headache)
Additional/secondary pharmacological effect (QT length) Triggering an immunological response (anaphylaxis)
What are the limitations of pre-marketing clinical studies and adrs
Evaluating the safety and secondly the efficacy of a new therapeutic
• Small number of patients
• Limited by age and possibly gender
• Selected following precise diagnoses
• Short, well defined duration
• Specialist doctors and continuous follow-up
• Concomitant therapeutics usually excluded
Describe teh spontaneous reporting o adrs
• …..Developed in response to the thalidomide tragedy
• Primarily producing a signal that creates further questions
• False positives and negatives – further analysis
• Number of ADRs reported annually through the MHRA ~ doubled cf. 2007
• Pharmaceutical companies, the published literature (pre-clinical)
• Yellow card scheme in place to report:
recently introduced products – all suspected ADRs inc. minor ones, all reactions to vaccines
Established products – serious or unusual suspected reactions (life threatening, disabling or prolonging hospitalisation
What are. The rods and cons of reporting adrs
- Simplicity – all drugs all of the time
- Timely and theoretically inexpensive to administer
- Detects both common and rare reactions
- Accessible by all health care professionals (patients and carers too)
- Inevitable and unquantifiable under-reporting
- Positive bias – serious, unrecognised or new drugs (good)
- Duplication
- Effect of publicity
- Incomplete poor quality data
- Other methods include Cohort, Case Control studies, Systematic Reviews (see Prof. Holland Dr Hsu and Dr Owen’s lectures)
How can reporting be improved
- Responsibility of all of you…..
- Being aware and interested
- Implementing suggested guidance and monitoring in high risk situations
- Integrated approach including multidisciplinary teams
- MUR and CMR
- Targeting and collecting data from under reporting areas – hospitals and particularly oncology – understand why this is so?
- Global approach – large data sets and sharing, particularly for serious but rare ADRs
- REPORTING OF TRIAL DATA, TIMELY AND COMPREHENSIVELY – GOOD OR BAD
What is pharmacogenetics
- How an individual gene may affect response to a drug or indeed the drugs response on the body – PK and PD
- Pharmacogenomics – more broadly the whole genome and affects on drugs – considering epigenetics
- Understanding of phenotypic differences and how they affect therapeutics is now moving at considerable pace
- Generally, therapeutic decisions made based on population level evidence
- It follows that treatment will not necessarily be effective nor that it will be safe in entire populations
- Further understanding and consideration of PG in combination with PV to reduce preventable ADRs
Describe teh influence of pg
• Person-person variability contributes to some of 7% serious ADRs and 3/1000 fatal reactions
• Drug reactions make up a not insignificant number of hospital deaths – some of which will be related to pharmacogenetics
• Understanding why particular patient populations do not respond to therapeutics – responder rates - is lacking – but improving
statin response limited in ~ 3/10, similarly ~ 4/10 limited response to β- blockers
• Identifying patients who may not respond or should be tested
• Effect can be to change drug – issues with screening/cost/facilities
Give examples of improving patient care
• Abacavir was associated with hypersensitivity in ~ 8 % patients treated for HIV – identified as a split antigen reaction
screening for the split antigen resulted in 75 % reduction in reactivity
• Cutaneous reaction (Stevens-Johnson syndrome or more severe toxic epidermal necrolysis) in patients taking carbamazepine – identified as a reaction to another split antigen – predominantly found in Asian patients
Gve an example of atihypertesive treatment
- Generally what is seen at whole population level
- RAAS activity dictates this response
- __________ typically lower in African Caribbean populations so (A) not primary choice for BP↓
- Angioedema more prevalent in African Caribbean populations than in young white Caucasians
Descrbe genetic polymorphism
• Both PK and PD can be effected
- changes in ADME and/or receptor structure, enzyme activity, immune response
• Aldehyde dehydrogenase deficiency – mutated ALDH2 – single aa change important in maintaining low blood acetaldehyde concs. during alcohol metabolism; highly prevalent mutation in oriental populations – effects of hangover can be much greater for similar EtOH consumption
• Metabolic enzymes (particularly CYPS) and their variations have been best characterised
• Warfarin and INR (see Lecture 12) Racemic mixture between S and R. S 3-5 times more potent and metabolised by different CYPs
Give cup 2d6 as an example
• The CYP 2D6 isoform is responsible for the metabolism of ~25% of drugs, including certain antidepressants, antipsychotics, β-blockers and opioid analgesics
• Variability in the rate of drug metabolism by CYP 2D6 is >100-fold
• 6% of the Caucasian population carrying two null alleles at the CYP 2D6
gene locus19. There are >70 variant alleles of the CYP 2D6 locus
• Other variants that decrease activity, alter substrate specificity or increase activity have also been described
• Reduction in or altered activity of CYP 2D6 can lead to ADRs by following MOA:
decreased first pass metabolism – metoprolol and bradycardia accumulation as a result of reduced metabolism
Re-routing of metabolism – paracetamol and toxic NAPQI intermediate (see lecture 17)
Describe the efficacy and toxicity
Ss
How can pg knowledge be used in therapeutics
• Personalising drug therapy
rapid screening of gene variants
knowledge of the genetic sequence of specific target receptors/enzymes
• Utilising this information in primary and secondary care – guidelines not always there
• Cancer – targeting particular somatic changes in neoplastic cells
• Statins – use for predicting ADRs – specifically muscle damage 1/1000 improved outcomes through tailored and managed therapeutics and adherence
• Other examples vaccines for allergies? Address prophylactic viral vaccine failure and ADRs by following genetic polymorphisms and their effect on innate and adaptive immune response
