WEEK 6 - Precision / Individualised Dosing Flashcards
(18 cards)
What is the difference between Personalised (individualised) Dosing and Stratified Dosing
Personalised Dosing
Takes into consdieration:
- Explained variability
- Unexplained variability
- PK and PD
- Therapeutic drug montioring (TDM
- Target conc. intervention
Expensive process
Stratified Dosing
Takes into consideration:
- Eplained variability
- PK and PD
- TDM
Straightforward
Describe the importance of concentration in clinical pharmacology
- Useful in Drug Monitoring
- i.e. steady state conc., minimum conc. - Monitor Therapuetic Window
- Range between min. effective and max. safe drug conc. / dose
- Can be wide or narrow
- To minimise SE / ADRs - Balance between efficacy and toxicity
NOTE:
- Clinical effects are caused BY CONC. not dose administered
- as conc. ↑ = effect ↑ AND SE risk ↑
- Conc. usually measured from plasma or blood
- if site of action is not these sites = be careful with interpretation
Explain the relationship between effect and drug conc.
Effect is caused by conc. not dose adminstered
- Plasma conc. ↑ once drug is in body
- Drug begins to produce effect
- Effect ↑ and reaches therapeutic window
- Elimination occurs = plasma conc, begins to ↓
- Drug falls below therapeutic window = enters sub-therpeautic region
NOTE:
- If bolus dose is given to reach Css (an infsuon follows to maintain steady state)
PK and PD Info
PK - How body affects drug
PD - how drug affects body
PK and PD target levels can be used to modify pt doses
= why doses differ between individuals
- Require detailed info about PK and PD for dose optimisation
List sources of variability
Can be intrinsic (I) or extrinsic (E)
- Genetics (I)
- polymorphisim in metabolising enzymes
- lack of enzymes - Demographics (I)
- Age, Gender, Weight, Ethnicity - Environmental (E)
- Smoking, Alcohol, Diet - Co-morbidities (I)
- DDIs, Disease, Pregnancy, Hepatic / Renal function
Explain the concept and importance of variability in PK and PD
Variability in Pts explains differences in effects produced
- e.g. may be given same dose but only some reach therapeutic window, other reach toxicity or sub-therapeutic
Equation (on NOTES)
- Total Variability (VT) affects plasma conc.
- Predictable (info we know) + Unpredictable variability = VT
Example: 5-Fluorouracil (5-FU)
- Used in colorectal + oesophageal cancer treatment
- Has NARROW therapeutic window
- has severe toxicity SE inc. cardiotoxicity, neurotoxicity
- Has short half life
- Dosing / monitoring is complicated due to variability in PK
- diff type of DPD metabolisers
5-FU Biotransformation
inc. DPD and DPYD
- 5-FU is eliminated / brokendown by DPD enzyme via liver
- 20% = kidney elimination
- 80% = liver elimination
- If pt lacks DPD enzyme = 5-FU conc. remains high
- Have DYPD genetic tests before giving pts 5-FU
- determine DPD activity
- determine dose regime e.g. reduced dose, normal dose, or avoid use - DPD activity varies in diff. ethnicities and gender
- ↑ activity in males = metabolise quicker = ↓ conc. levels
NOTE:
- DPD is encoded by DPYD gene
- Genetic polymorphisim (variants) in DPYD gene = ↓ or loss of DPD activity = variability
- High levels of 5-FU = toxicity
Explain the phenotype, activity socre and genotype for different DPYD activities
Example
Phenotype and Activity score:
- Normal metaboliser = 2
- Intermediate metaboliser = 1 or 1.5
- Poor metaboliser = 0 or 0.5
Genotype
- Normal = 2 normal function alleles
- Intermediate = 1 normal and 1 functional, OR 1 normal and 1 reduced function OR 2 reduced function
- Poor = 2 no function OR 1 no function and 1 reduced function
List approaches to Individualised Dosing
Takes into consdieration:
- Explained variability
- Age, Gender, Ethnicty
- Renal / Hepatic Impairment
- Genetic variants
- Drugs, Alcohol, Smoking
- Unexplained variability
- PK and PD
- Therapeutic drug montioring (TDM
- Target conc. intervention
- take plasma conc. reading frompt to see if conc. is within range wanted
- if too high = ↓ dose
- if too low = ↑ dose
All the above are used to inform dosing
Carry out calculations for dose adjustment using covariate information
Covariate = an independent variable that can influence the outcome
Example:
- Weight
- Renal function
- Age (esp. in babies and infants)
6-Mercaptopurine (6-MP)
- Use in leukaemias (ALL, APL) and Crohn’s disease
- Has NARROW therapeutic window
- Toxicity inc. bone marrow supression, liver toxicity, cancers - Has high variability due to genetics
NOTE:
- 6-MP needs to enter RBCs to have its effects
Explain the biotransformation of 6-MP
biotransformation= change from one chemical to another (like metabolism)
6-MP is metabolised by 3 enzymes:
1. TPMT
- found in liver, kidney, RBC, platelets
- genetic polymorphisim in TMPT gene = reduced / no functioning enzyme
2. Xanthine oxidase (XO)
- inhibition with Allopurinol = bypass ↓ 1st pass metabolism = ↑ metabolite
- found in liver and gut
3. HGPRT
What 2 metabolites are formed:
1. TGN (mostly active)
- produces effect ~ efficacy + safety
2. 6mMPN
What is the role of TPMT enzyme
TMPT metabolises 6-MP into a metabolite that is not the active metabolite of the drug
- i.e. not TNG
Lack of TMPT = 6-MP not metabolised = more active metabolite = ↑ SE / toxicity
Explain the polymorphism in TPMT enzyme activity
3 Types of activity, Contributing factors, Doses for each group
- Normal activity (wt) ~ 500mg/m2/week
- i.e. 2 functional alleles
- i.e. 1/1 - Intermediate activity (wt/v) ~ 250mg
- i.e. 1/ 2 or 3a or 3c - Poor/no activity (v/v) ~ 25mg
- i.e. *2/ 2 or 3a or 3c
Contributing factors:
- Ethnicity (afro-americans have ↓ TMPT expression)
NOTE:
- Pt have genetic testing for TMPT variants
- In variant groups an amino acid on allele has been substituted incorrectly = TMPT not expressed
- Alleles are inherited from parents
- e.g. 1 parent has activity and other doesnt = will have 1 functional and 1 non
Explain the link between TPMT enzyme and response
Efficacy and toxicity
↓ TMPT enzyme activity = ↓ 6-MP metabolism = ↑ TGN metabolite
- ↑ TMPT = ↓ TGN
- ↑ TGN = ↑ efficacy AND ↑ toxicity
May have genetic polymorphism / varaints in TPMP gene = varaibility
- some pts may expereince toxicities or sub-therapeutic effects
Explain the link between exposure and clearance in TPMT polymorphic groups
Pts with ↓ TMPT = ↓ 6-MP metabolism / clearance = ↑ TNG metabolite exposure
Pts with intermediate / poor TMPT levels require dose reductions
Future Studies for dose individualisation
Digital Twins
- combines demographics, phenotype, genotype, intrinsic and extrinsic variabilities to determine dose
