Theme 5: Pharmacokinetics (L21&22) Flashcards
1
Q
What are the problems in dosing drugs?
A
Compliance
Dosing and medication errors
Absorption
Tissue and body fluid mass and volume
Drug interactions
Elimination
Drug metabolism
2
Q
What are the different factors affecting drug effects?
A
Drug receptor status
Genetic factors
Drug interactions
Tolerance
3
Q
What is the order of drug processes?
A
Absorption
Distribution
Metabolism/excretion
4
Q
How can blood samples be modified to study PK data?
A
Separation of plasma
Ultrafiltration (separate bound and unbound drug)
Derivatization (stabilise active metabolite)
5
Q
What are the different techniques to analyse PK data?
A
HPLC (chromatography) - UV detection (ug/ml)
HPLC - fluorescence detection (ng/ml)
LC-MS (mass spec) - specific mass detection (pg/ml)
Atomic absorption spectrometry
6
Q
What do concentration-time profiles show?
A
The relationship between drug exposure, toxicity and response
7
Q
What does the drug in plasma reflect?
A
Active drug (concentration - effect)
Drug available for elimination
Drug equilibrium with body
8
Q
What are the main types of PK data analysis?
A
Noncompartmental analysis
Compartmental
Population models
Physiology-based
9
Q
What is non compartmental analysis of PK data?
A
Does not assume any number of body compartments (PK profile and area under curve)
10
Q
What is compartmental analysis of PK data?
A
1,2 or 3 compartments
Tissue lumped in compartments (maths)
How fast conc reaches equilibrium with blood conc
11
Q
What is population model analysis of PK data?
A
How individuals from population vary
All data considered same time (unified model)
12
Q
What is physiology-based analysis of PK data?
A
Each major organ/tissue group of body has own compartment
Arranged anatomically
13
Q
What is the equation of the line in concentration of drug over time graphs?
A
C = -k*t + C0
k - rate constant (always negative as loss of drug over time)
14
Q
What is zero order elimination?
A
Elimination of constant amount of drug per unit of time (rare reactions)
15
Q
Why are elimination rates used?
A
To predict how a drug concentration in the plasma changes with time
16
Q
What is first order elimination?
A
Constant proportion of drug eliminated in defined time period (all PK processes follow)
17
Q
What is absorption of a drug?
A
It is the transfer of an exogenous compound from site of administration to systemic circulation
18
Q
How are drugs absorbed?
A
Across cell membranes:
Passive diffusion
Active transport
19
Q
Which compounds are absorbed more readily?
A
Lipid-soluble and unionised
20
Q
What is Cmax and Tmax?
A
Cmax: maximum concentration of compound after administration
Tmax: time at which Cmax is reached
21
Q
What is AUC?
A
Area under curve
Measure of systemic exposure
Units - concentration*time
22
Q
How is AUC calculated using trapezoid?
A
A = (C1+C2/2)*(t1-t2)
23
Q
How is full AUC calculated?
A
AUC = Ct/k
Ct - final known concentration
k - first-order elimination rate constant
24
Q
What is bioavailability?
A
Measurement of extent of absorption after extravascular administration
IV = 100%
Calculate using AUC data or urine
25
How is bioavailability calculated?
F = AUC oral/AUC x doseIV/dose oral
26
What is the absorption rate constant?
Measure of speed of absorption
Calculation: (difficult to estimate)
Wager-Nelson method
High Ka = faster absorption
27
What is distribution of a drug?
From systemic circulation to other tissues which is impacted by:
Cross cell membranes
Blood flow
Plasma protein binding
28
What is the free drug hypothesis?
Only free drug can exhibit pharmacological effect
29
How does protein binding impact distribution of drugs?
Only unbound drug is able to diffuse through cell membranes to interact with receptors
Greater binding results in larger volume of distribution
30
What is volume of distribution?
Measure of extent of distribution
Dilution factor - amount of compound and plasma concentration
Units of volume (sometimes per unit of weight)
31
How is volume of distribution measured?
V=dose/C0
V=CL/k=dose/AUC*k
T1/2= 0.693*V/clearance
32
Why is volume of distribution relevant?
Due to binding of drug to plasma proteins (binding = lower Vd)
33
What are examples of the volume of distribution of drugs?
Heparin 0.05-0.1L/kg
Warfarin 0.1-0.2 L/kg
Phenytoin 0.7-0.9 L/kg
Paracetamol 1-2 L/kg
Morphine 2-5 L/kg
Chloroquine 200 L/kg (drug in lipid molecules)
34
What are the mechanisms of elimination dependent on?
Physiochemical properties:
Volatile gases - exhalation
Water-soluble - unchanged in urine (+bile)
Lipid-soluble - metabolism to more soluble then urine/bile
35
What is saturable elimination?
Not typically saturated at therapeutic dose (although phenytoin does)
Increase dose = increase concentration
Michaelis-Menten kinetics
36
What is clearance?
Ability of the eliminating organs to remove compound from body
Volume of plasma cleared of the compound per unit of time
37
How is total body clearance calculated?
Sum of all organ CL processess
38
How is clearance calculated after IV and oral dosing?
IV:
CL=IV dose/IV AUC
Oral:
CL=Oral dose*F/Oral AUC
39
What is the elimination rate constant?
It is the log-transformed data of a concentration-time profile
Units - 1/time
40
What is half-life?
It is the time it takes for the concentration of a compound to reach 50% of its current value
t1/2=0.693/k
41
How long does it take for a compound to reach steady state after chronic exposure?
5 half-lives
42
What is the relationship between clearance, volume of distribution and half-life?
CL and Vd are pharmacokinetic parameters (independent) but they determine half-life
43
How is PK data handled?
Using compartment models
44
What does a compartment model include?
Uses date from PK profiles
Has features like:
Exponential equations
Theoretical compartments and transfer rates
Used for simulations (kinetically similar tissues)
45
What do compartment models determine?
Clearance
Bioavailability
Absorption rate
Distribution profile
Terminal half-life
46
What is the one compartment model?
Linear process
All tissues/organs lumped into one compartment
47
What is the two compartment model?
Body doesn't conform to 1 compartment
Represent a similar group of tissues/fluids
More flexibility
Processes of distribution and elimination
48
What best describes the time course of a drug?
One-, two- or multicomparmtnent models simply reflect the best way
49
What is the central and peripheral compartment?
Highly perfused organs (e.g.heart, liver and kidneys) similar distribution patterns
Central compartment includes blood, heart, lungs, liver and kidnets
50
Which 2 parameters determine half-life?
Distribution and elimination
51
How are population pharmacokinetic models used?
Provide understanding of how individuals from a population differ
All data considered the same
Features:
Intensive and sparse sampling
Computationally intensive
Longer analysis time
Allow provision for PK/PD modelling
52
What do population pharmacokinetic models determine?
Clearance
Volume of distribution
Effect of covariates
53
What are the advantages and disadvantages of individual PK model?
Advantages:
Simple
Robust
Model-independent
User-friendly software
Rapid
Disadvantages:
Assume linear PK
Model-independent
Single analysis
Study design limits
54
What are the advantages and disadvantages of population PK model?
Advantages:
Robust
Structural model PK/PD
Any administration route
Linear/nonlinear PK supported
Descriptive and predictive
Disadvantages:
Less rapid
Less user friendly
More expertise for analysis
55
How does physiology-based pharmacokinetics differ to traditional methods?
Composed of a series of compartments representing organs/tissues drug concentrations uniform
Extrapolate in vivo from in vitro
Estimation drug time course in organ in model
Simulation of dosing, clinical trials, drug interaction, parent and metabolite PK
56
What are system parameters in physiology-based pharmacokinetics?
Tissue volumes and blood flows
Tissue composition
Intestinal pH, transit times
Enzyme/transporter abundance
57
What are population and external factors in physiology-based pharmacokinetics?
Age, gender, race
Disease status
Genetic status
Drug-drug interactions, smoking/diet
58
What are drug-dependent parameters in physiology-based pharmacokinetics?
LogP, pKa, B/P, molecular weight
Permeability
Solubility, particle size
CLmet, CLdiff, CLact,uptake
59
What can physiology-based pharmacokinetics be used for?
Simulation of clinical trials without clinical data
Estimation of tissue specific concentrations
Assessment of potential for drug-drug interactions
60
In drug development when is pharmacokinetics investigated?
In vivo, in man (clinical phase I), in clinic (stages of clinical trial)
61
What is allometric scaling?
Using animals to scale how drugs will react in humans
62
What are the features of allometric scaling in pharmacokinetics?
Small animals tolerate relatively larger doses due to rapid drug clearance
Longer half-life in humans equated to inc. tissue exposure
Limitations in terms of available volumes of blood for studies
63
What are the features of phase I clinical trials?
First in human use
Dose escalated over time
15-30 individuals/patients
Ensure new medicine presents no major safety issues
Clarify drugs reach targeted body area and remain there long enough to deliver benefits
Gain preliminary evidence for therapeutic benefit
64
How are phase I trails designed?
Dose administered in humans linked to non-toxic dose animals
Subsequent dose-escalation as multiple first dose
65
What is the rationale for PK/PD studies?
Although the same dose may be given with the same pharmacokinetics the pharmacodynamics in the patient may differ as rate of clearance can vary
66
How can PK/PD models show the concentration of crizotinib in plasma correlates to ALK/MET inhibition?
Using rate-limiting distribution of crizotinib from blood to tumour
EC50 values for ALK and MET inhibition
50% ALK inhibition needed for anti tumour in contrast to 90% MET inhibition
MET is a better target
67
What are the concerns for dosing in young patients?
PK differences
Toxicity profile
Development of major organ function
Dose reduction for age
- Cancer drugs only given in late stage
68
How can comparing drugs between infants reveal different pharmacokinetics?
Carboplatin: quicker clearance therefore a lower effect
Daunorubicin: no significant difference between exposure to each of the drugs
69
What are the guidelines for dosing carboplatin in infants with retinoblastoma?
When utilising carboplatin there is either the accessibility for therapeutic drug monitoring or not
Doses therefore vary between patients based on their factor to increase or reduce dosage based on efficacy and toxicity
70
How do properties of pharmacokinetics differ in obese patients?
Can change incidence on disease like cancer and therefore treatment and long term morbidity
Prescription of drugs may differ
Pharmacokinetics of particular doses may be impacted
71
How is dose based on PK?
Toxic and therapeutic effects related to plasma concentration
Patients characteristics determine PK/metabolism
Individualised based on:
renal function
hepatic function
genetics
72
How does AUC and clinical effect differ in carboplatin dosing?
Cumulative dosing allows monitoring of toxicity
73
How is dosing of carboplatin related to GFR?
The dose is provided through the formula:
Dose = AUC x (GFR+25)
Since it is eliminated renaly as a free drug the levels have to be measured on an individual basis
Body surface area can cause large spread in dosing as opposed to renal function
74
How do other drugs differ too carboplatin?
Simple elimination (no metabolism)
Simple mechanism of action (Pt-DNA adduct = AUC) = efficacy
Target exposure in other drugs
75
How can hepatic function tests be used to find correct dosing?
Raised bilirubin/liver function enzymes indicate hepatic dysfunction
-metabolism
-biliary excretion
Hepatic impairment in cancer
-liver disease/metastases
-biliary obstruction
-drug side effects
76
How can hepatic and renal clearance impact elimination and therefore dosing?
If clearance is lower then exposure to the drug is higher therefore there has to be adjustments in dosage in each patient individually
77
What is an example of drug-drug interaction with CYP3A4?
Simvastatin and grapefruit juice
10x exposure simvastatin
78
What are the benefits of therapeutic drug monitoring?
Variable/unpredictable relationship between dose and plasma concentrations
Narrow therapeutic window
Correlate measured drug with efficacy/toxicity
Availability of reliable and clinically feasible assays
79
Where is therapeutic drug monitoring used clinically?
CVD
HIV/AIDS
Epilepsy
Infection/septicemia
Respiratory disease/ asthma
80
What is the rationale for therapeutic drug monitoring in cancer?
Major public health issue
Narrow therapeutic window - systemic exposure toxicity and response
Large degree of inter patient variability in drug disposition
Examples of clinical benefit of TDM
Established use of old drugs and increased importance of long-term toxicity with increase in cancer survivors
81
What are the properties of cabroplatin monitoring?
SimplePK GFR=elimination
Formula derived to calculate dose for specific exposure
Target AUC 5-7 mg/ml.min
Toxicity and response closely related to AUC vs administered dose
Feasible pharmacological dosing for high dose carboplatin
82
What is the process of real-time drug monitoring?
Same dose 1-2 days:
Initial dose based RF
PK sampling
Measure carboplatin concentrations
AUC determined
Dose changed 3rd day:
Recommended dose adjustment
83
Why is dose adjustment important
When doses are adjusted due to TDM there is a smaller chance of toxicity being reached
84
How has the therapeutic window changed in carboplatin dosing?
Increased percentage of patients in the TW following TDM vs standard approach
85
How has vincristine dosing been altered in younger patients?
Large variability in dosing
No significant difference in clearance between infants, neonates and older children
Significant differences in exposure
Therefore it should not be initiated below 0.05mg/kg
86
How was 13-cisRA bioavailability and PK changed for younger patients?
Formulation changed to liquid flavoured to provide treatment to children under 2 years that cannot swallow - created 65% bioavailability
