Lecture 15- Precision Medicine II Flashcards
Pharmacogenomics
Pharmacogenomics (PGx)- part of precision medicine and studies how genetic variation affects response/interaction with drugs
PGx + genomic bedicine = linked as a patients disease genetics relates to genes that are targeted for treatment / impact drug interactions
Pharmacogenomics in clinical practice
PGx combines pharmacology + genomics to develop effective, safe meds that can be prescribed based on a persons genetic makeup
Adverse drug reactions
Excludes therapeutic failures; overdose, drug abuse, non compliance + med errors
Important since they are one of the leading causes of morbidity + mortality in health care
-4th leading cause of death
-have significant media exposure
Patient care may suffer/ may lose confidence in a drug
Most ADRs are detected in premarkerting clinical trials which are reported in prescribing info but latent ADRs are often missed
Trials exclude the young + old, pregnant women + patients with co-morbidities + polypharmacy
Risk factors;
-simultaneous use of several different drugs + drug-drug interactions
-very young/ old
-preg/ breastfeeding
-co-morbidities/ disease states which may affect ADME
-genetic factors
Pharmacogenomics testing
PGx= integrates genomic info into drug development + prescription
PGx testing = determines drug response/ADRs + function as genetic biomarkers in FDA drug labelling
PGx testing success + benefits
Safer use of existing medicines- slide 13
Benefits;
*Reduces hospital admissions- slide 14
*Clinical trials; genetic biomarkers used in clinical trials for; proof of efficacy, optimisation of dose + safety and tolerability
PGx in healthcare; stakeholders
Stakeholder roles within the healthcare system that have an interest in clinical decision making;
-regulator, pharmacist, clinicians, patient, hospital, payer, wholesaler and therapeutic/diagnostic manufacturer
Pharmacists;
-work in community, industry + hospitals
-provide value by understanding + managing patients total drug profile
-point of care; for dosing + administration and warn of potential ADRs
-speciality pharmacies= provide assistance to patients
PK + PD
PK= absorption, distribution, metabolism + excretion (ADME) - describes how the body handles a given drug + this determines the drug-plasma over time
Slide 20
Drug metabolising enzymes;
Cytochrome P450 superfamily isoenzymes
Most important metabolic enzymes with clinically relevant genetic variation
CYP= highly polymorphic + impact the functional activity of several isoenzymes
Combination of alleles- used to classify individual metabolising status/phenotypes + can include active, partially active, inactive + overactive forms
Metabolising status/ phenotypes
Slide 23
Clinical consequences of altered enzyme activity/ status depends on whether;
- the pharmacology activity resides with the parent drug or the metabolite of a prodrug
- the enzyme is susceptible to inhibition by the drug
Active drug vs Prodrug (bioactivation)
Number of drugs are administered as a prodrug and need to be bioactivated before they can exert their effects whereas conversion from the parent compound in either the gut/liver occurs before reaching circulation
Efficient conversion= good E of the active drug (EM)
Inefficient conversion= more parent compound will reach circulation
Over efficient conversion= ??
Drug metabolising enzymes
On chromosome, 22 translates to a 497 AA enzyme that metabolises over 100 drugs including;
- antidepressants; fluoxetine
- neuroleptics; haloperidol
- beta-blockers; propranolol
- analgesics; codeine
CYP2D6*1= Wild-type allele and phenotypically considered as EM and normal where the key loss of function alleles is *4 (inactive) and phenotypically PM
^more on CYP2D6 variants on slide 26
CYP2D6
Clinical complications;
- individuals with PM polymorphisms may require reduced dosing in order to avoid toxicities due to decreased metabolism which can be severe/ fatal
- individuals with UM polymorphisms may require the polar opposite therapeutic course through Inc dosing = avoid symptoms of drug in efficacy
- highlights of the potential of PGx - provides a mechanistic basis to why individuals belong to a specific ethnic group may respond very differently to a given drug + may allow a means for more precise dosing
PGx + ADRs; codeine/ morphine
Morphine; analgesic used in moderate-severe pain
Patients initially administered the PRODRUG codeine; methylmorphine
Codeine= metabolised in the liver by cytochrome P450 2D6 where the enzyme demethylates codeine into active drug- morphine
Codeine/Morphine dosing guidelines
Patients with different genetic versions of CYP2D6 gene affect the enzymes ability to convert the prodrug to codeine to morphine
^may leave some patients having a reduced/no pain relief response while in others morphine will act as a proficient analgesic, side effects!!
Drug transporter proteins
Drugs available for absorption may be ‘taken up’ through the GI wall + distributed to the portal blood flow by influx and efflux transporters and are subject to genetic variation like the metabolising enzymes e.g. CYP2D6
Transporters can also impact bioavailability; 2 fams
*solute carrier (SLC) transporters e.g. organic anion transporting polypeptides OATP1
*ATP binding cassette (ABC) transporters e.g. P-glycoprotein (P-gp)
Pharmacodynamics
Slides 33-34
PGx + enzymes as drug targets; ALOX5 + CCR5
Rest of slides
