End of semester test Flashcards
Target concentration
Target concentration approach links PK with PD to predict the right dose for a patient. A target effect might be pain relief. Ideal dose prediction requires individual estimates of Emax, C50, V and CL. To find the target you randomises concentration controlled trials. PK/PD varies because of systematic (body size, disease state and genotype) and Random (between/within-subject variability) variables.
= (Target effect x C50)/(Emax - target effect)
Theophylline is metabolised by
CYP1A2, which is induced by polycyclic hydrocarbons in cigarette smoke. Enzyme induction reduces variability because there is a max biological limit in the extent of enzyme induction.
Three ways to dose: population
Is commonly used, but patients all receive the same dose, meaning that some patients are over/under dosed.
Three ways to dose: Group
Is when the same dose for similar groups is given, e.g. the same weight, CLcr (CL creatine) and genotype (more so in kids)
Three ways to dose: Individual
Dose is determined by individual response e.g. by BP, international normalised ratio, blood concentration. Used when the within-subject variability is large and predictable individualisation is not really possible.
INR
measures the degree of change in coagulation properties of blood
Target clearance
- Uses responses such as BP as a substitute for being able to measure the clinical disease state that is being treated.
- When medicine is working well or not working at all the clinical disease state may appear to be the same.
- Is used when group based dosing is not enough to reduce the between-subject variability so that the drug can be used safely and effectively.
- Can only work however is the within-subject variability is small enough so that dose individualisation is really predictive for future use of the medicine in the same patient.
Measuring Concentrations
The least informative time to do this is just before the next dose (trough) unless this is paired with another peak. This is because CL determines the average concentration, so measuring concentration in the middle of the dosing interval will be closer to the average and therefore better at predicting CL. A concentration in the middle of the dosing interval (Ctmid) will be closer to the average steady state concentration (Css) then either a peak or a trough. CL= does rate/Css which is approximated by CL= Dose rate/ CTmid.
Gentamicin and dosing intervals
Concentrations vary widely in a dosing interval so two concentrations are needed to reliable estimate CL. The trough concentration at 24h is often unmeasurable because it is below the limit of quantitation. Concentrations are best measures 1h and 8h after the dose.
Therapeutic drug monitoring
Traditional concept, that if the dose is within the therapeutic range then it is not adjusted. A concentration at the bottom of the range (ineffective) is very different from one at the top (possibly toxic), but TDM usually ignores this and are happy to do nothing as long as it is within range.
Target concentration intervention:
Is a science-based method that uses PK and PC principals to identify who patients are different and uses PK-guided does individualisation to achieve a precise target. It has been shown to improve clinical outcome as well as being cost effective.
Three was to think about time course effects
- Drug effects are immediately related to observed drug concentration
- Drug effects are delayed in relation to observed drug concentration
- Drug effects are determined by the cumulative action of drug
Law of mass action
the binding of a drug to a receptor should follow a hyperbolic curve, it is assumed that effect is directly proportional to the binding then the C50 will be the same as Kd
Kd
is the equilibrium binding constant, and the concentration at which 50% of the binding sites are occupied
Emax model
E = (Emax x conc)/(C50 + conc).
- The model is the description of a concentration-effect relationship.
- An important prediction of the model is that all biological systems will reach a maximum.
- Many drugs will have a steeper concentration and effect relationship so that a smaller change is required to see the same change.
The sigmoid Emax model
E = (Emax x conc^hill)/(C50 + conc^hill).
This model is showing 4 different values for the hill coefficient.
When hill >10
The concentration effect relationship is like a switch, the effect turns on at a threshold concentration close to the C50.
When hill = 2
It only takes a 4 fold change in concentration to go from C20 to C80.
When hill <1
the curve is shallower than Emax
When hill >1
the curve is steeper than Emax
When hill = 1
the curve is the same as the Emax model
Conc peak = 10 x C50
This shows how the time course of immediate drug effect depends upon the initial concentration as well as the PK of the drug. Shows the time course concentration after a bolus dose at time zero. Initial conc is 10 x the C50 and produces and effect that is 90% of Emax. After one-half life, the concentration is halved but the effect has changed by less than 10%. As conc falls the effect disappears more quickly
Conc Peak = C50
Initial concentration is the same as the C50 then the initial effect will only be 50% of Emax. At these lower concentrations, the time course of effect is almost parallel to the time course of concentration.
Conc Peak = 100 x C50
When a very big dose is given, the initial effect is close to 100% of Emax. The effect changes very little despite the big changes in drug concentration. After more than 5 half lives when nearly all the initial does will have been eliminated the effect will still be 70% of Emax. This is common for receptor agonists.