Clinical Pharmacokinetics lab

Clinical Pharmacokinetics

Important parameters:
Volume of distribution.
Clearance.
Half life.
Bioavailability.

Volume of distribution: (Vd):

It is more precisely called the apparent volume of distribution as it represents the imaginary volume through which the drug would be fully distributed to account for the measured plasma or blood concentration.
So, it is a theoretical rather than a real space.
Vd = amount of drug in the bodydrug concentration in blood or plasma
Vd = DC0
D = dose, C0 = concentration at t0
Example:
A 500 µgm dose of Digoxin was given to a patient, after which the plasma concentration of Digoxin was measured and found to be 0.7 ng /ml.
Vd =500o.0007 = 714 liter.
It is very clear from this example that the calculated Vd is much higher than the overall body volume.
Clinical importance of Vd :
1-Drugs with high Vd usually have high lipid solubility and are sequestrated in fatty tissues and thus less available to the systemic circulation which makes them having a relatively long half life and prolonged duration of action.
2-Vd is used to estimate the initial dose of the drug needed to achieve therapeutic plasma concentration at the beginning of treatment (loading dose).
Loading dose = Vd × Target concentration
3-Several conditions could alter the Vd and thus change the kinetics of the drug, examples of such conditions are renal failure, liver failure, dehydration, low plasma protein concentration, hyperlipidemia and many others.


Clearance (CL):
Clearance is the most important concept in clinical pharmacokinetics; it represents the volume of blood or plasma which is completely cleared from the drug per unit time.
This concept is very similar to creatinine clearance in physiology.
CL = Rate of eliminationConcentration of the drug , and so
Dosing rate = CL × Css
Css=concentration at steady state.
In clinical practice clearance can be used to calculate the maintenance dose of some important drugs.
Example of maintenance dose calculation:
A target plasma Theophylline concentration of 10 mg/liter is desired to relieve acute bronchial asthma in a patient, if Theophylline clearance=2.8 L/h, what is the maintenance dose of intravenous Theophylline needed to improve the patient?

Dosing rate = CL × Css = 2.8 × 10 = 28 mg/hour

Therefore in this patient the proper intravenous infusion rate would be 28 mg/hour.
If the attack was relieved and the physician wants to maintain the treatment with oral Theophylline which is given every 12 hours by capsules, what would be the dose of oral Theophylline?
Maintenance dose = dosing rate × dosing interval
= 28 × 12 hours = 336 mg every 12 hours

Half life (t1/2):

It is the time needed for the concentration of the drug in the blood to be reduced by 50%.
t1/2 = 0.693 × VdCL
Half life is an important parameter because it gives the clinician a very clear knowledge about the fate of the drug after being administered, thus knowing the half life of a drug will help in designing a safe and effective dose regimen.
Most drugs achieve steady state concentration in plasma (Css) after 5-6 half lives.


Example:
An intravenous dose of Ceftriaxone was given to a patient and the following plasma concentrations were measured:
C 0 50 µgm/ml
After 1 hour 45 µgm/ml
After 5 hours 35 µgm/ml
After 8 hours 25 µgm/ml
After 16 hours 12.5 µgm/ml
After 24 hours 6.25 µgm/ml
What is the half life?
Answer: (t1/2) = 8 hours.

Bioavailability:

It is the amount of the drug which reaches the circulation in an active form after oral administration; this amount is the fraction of dose absorbed (F).
Bioavailability = AUC oralAUC injected ×100 %

Area under the curve (AUC):

Area under the curve is derived from the plot of drug concentration in blood or plasma as a function of time.
It is useful in the determination of other parameters including volume of distribution, clearance & bioavailability.
Determination of (AUC):
Using computer software.
By cutting the curve and comparing the weight with standard.
Using an equation:
AUC=C0+C1t1-t02+C1+C2t1-t22+⋯⋯CnK
Cn: last observed plasma concentration
K: rate constant for elimination

Factors which affect the bioavailability:

1-pharmacetical factors
2-biological factors
3-presystemic factors (first pass metabolism in the liver).