An enumeration and brief overview of different pharmacokinetic parameters.

1. Pharmacokinetic parameters
Presented by-
Deepak Pandey

2. Outline
• Enumeration and brief overview of different pharmacokinetic
parameters-
• Absorption-
• Bioavailability
• Distribution-
• Volume of distribution
• Metabolism and Excretion-
• Clearance
• Half life and order of elimination
• Elimination constant
• Dosing regimens
• Therapeutic drug monitoring

3. Concentration time graph
• Peak plasma concentration
• Time of peak plasma
concentration
• Area under the curve
• Minimum effective
concentration
• Maximum safe
concentration
• Onset of action
• Time of onset
• Duration of action
• Intensity of action
• Therapeutic range
• Therapeutic index
Maximum

4. Bioavailability (F)
• Fraction of administered drug which
reaches systemic circulation in unchanged
form
• It is expressed as fraction or percentage and
can range between 0 and 1
• In a concentration time graph, the area
under curve (AUC) represents the total dose
of drug in plasma
• Thus, bioavailability can be calculated as-

5. Bioavailability
• Factors affecting bioavailability of a drug include-
• Particle size
• Degree of ionization and pH at the site of absorption
• Gastric emptying & GI motility (TCA and anti histamines)
• Food and other substances (Grapefruit juice and felodipine)
• First pass metabolism (Sublingual vs Oral)
• Drug interactions (Tetracyclines forming complexes with iron and antacids
in gut lumen, bisphosphonates with calcium)
• Route of administration
• Area and perfusion of site of drug administration (Muscle vs Fat)

6. Distribution of drug
• One compartment model-
• Few drugs (Aminoglycosides) are
rapidly distributed in tissues and
aren’t significantly accumulated in
tissues such that the entire body
works like a single compartment.
• Their plasma concentration will
decrease mostly due to clearance or
metabolism and thus they will show
continuous logarithmic decline in
concentration time graph.

7. Distribution of drug
• Two compartment model-
• Few drugs are slowly absorbed into
peripheral tissues like Vancomycin
and Digoxin.
• Their plasma concentration graph will
show two slopes of decline which are
of redistribution and elimination.

8. Distribution of drug
• Factors determining rate of distribution and amount of drug
distributed to different body tissues-
• Regional blood flow to the tissue
• Capillary permeability
• Volume of tissue and tissue selectivity of drug (Incorporation of
Bisphosphonates into bone)
• Extent of plasma protein binding of drug as only the unbound fraction is
available for transport into tissues
• Presence of barriers (Blood brain barrier)

9. Volume of distribution (Vd)
• It is an apparent volume available for
administered amount of drug to
disperse considering the whole human
body as a homogenous solution
• Volume of distribution = Quantity of
drug administered/ Plasma
concentration (C)
• It shows the extent of redistribution or
accumulation of drug in tissues
• Eg- Warfarin has low (Vd) owing to its
high plasma protein binding while
Chloroquine has high (Vd) because of
its accumulation into peripheral fat.

10. Volume of distribution
• It is used to determine the loading dose of a drug
• Loading dose = Target concentration X Volume of distribution
Suppose the target concentration of a drug is 15mg/ml and Volume of
distribution of the same drug is 30 L.
• Since, the Volume of distribution of a drug in a patient doesn’t depend on the
amount of drug administered or the route of administration, it will remain
same
Then, the loading dose will be 15mg/ml X 30L = 1.5g/L X 30L i.e, 45 g

11. Volume of distribution
• Factors affecting volume of distribution
• Lipid solubility of the drug
• Ionization of the drug at physiological pH
• Plasma protein binding of the drug
• Limitation- It is assumed that the concentration of drug in different
tissues corresponds to the plasma concentration and that the
response of drug varies in accordance with the plasma concentration
which may not be true in each case.

12. Kinetics of drug elimination
• First order kinetics (A) - The rate
of drug elimination varies
proportionately to the plasma
concentration of drug. Most of
the drugs follow this pattern of
elimination.
• Here, as plasma concentration of
drug decrease, the rate of drug
elimination decreases and vice
versa. (Rate of drug elimination is
the amount of drug removed
from blood per unit time)

13. Kinetics of drug elimination
• Saturation kinetics (B) - The rate of drug
elimination becomes constant after a
certain level of plasma concentration is
reached i.e., A fixed amount of drug will
be removed from blood in unit time. The
drugs include Phenytoin, Ethanol,
Salicylates
• For few drugs(C), (Valproate and
Disopyramide), as the plasma
concentration increases, the plasma
protein gets saturated and the
concentration of unbound drug increases
leading to disproportionately increased
elimination of drug

14. Clearance
• Volume of plasma that contains the amount of drug that is removed
from body per unit time
• Suppose, the rate of elimination of drug is 10mg/min and plasma
concentration of drug is 5mg/ml. Then,
Clearance = 10 mg/min/5mg/ml = 2ml/min i.e, 2ml of plasma is cleared of drug
every minute
• It remains constant for drugs showing first order metabolism
• The clearance of a drug include-
• Hepatic clearance
• Renal clearance
• Others

15. Clearance
• Factors affecting clearance of a drug include-
• Extraction ratio of organ (liver, kidney)- The
fraction of drug removed from plasma flowing
through the organ per unit of time. i.e., If a drug
X has a concentration of 15mg/ml in portal vein
(CA) and concentration of 10mg/ml in hepatic
vein (CV). Then, hepatic extraction ratio will be-
CA - CV/ CA = 5/15 = 1/3
• Plasma protein binding of drug
• Blood flow to the organ (liver, kidney)
• Functional state of kidney, liver
• Interactions with other drugs (enzyme
inducers/inhibitors)

16. Steady-state concentration
• When the drug is administered at a
constant rate or at regular intervals, the
cumulative accumulation of drug and
simultaneous elimination are balanced
and a steady concentration is reached
• For maintenance of steady state
concentration, the vol of drug that is
cleared of drug must be replenished
continuously. Thus, clearance is used for
calculating maintenance dose as under-
where, Cp is the plasma concentration of
drug, CL is clearance and F is bioavailability
of drug

17. Elimination rate constant (Ke)
• Fraction of drug that is excreted from the body per unit time
• Rate of elimination = Ke X Concentration of drug in plasma
• Thus, Ke = Clearance/Volume of distribution
• The relationship between concentration at a time t (C) after
administering the drug and the steady state concentration (Css) of the
drug is derived as-
• Thus, we can calculate plasma concentration at a time t by knowing
the elimination rate constant and steady state concentration of the
drug

18. Half life (t1/2)
• Half life of a drug is the time taken for its plasma concentration to
drop to half of the peak plasma concentration
• Half life of a drug determines
• Duration of action of drug after a single dose
• Time required to reach steady state concentration
• Dosing frequency
• For a drug following first order kinetics, the half life can be derived as-
i.e, the half life depends on both volume of distribution and clearance of the
drug

19. Dosage regimens
• Ideal dosage regimen- Dosing intervals and amount of drug given in each dose is such that the
plasma concentration of drug stays above the minimum effective concentration within the
therapeutic window
• The dosage regimen for different drugs is arrived through different ways-
• For drugs where physical parameters can be assessed (BP, Blood glucose), a trial and error
method is used where the dose and intervals are titrated accordingly
• Few drugs have wide range of therapeutic window (Penicillins) where maximum efficacy is
desired
• The change in plasma concentration (ΔC) after a single oral dose-
• Thus, the loading dose becomes-
• For maintenance dose-
(where T is the dosing interval)

20. Therapeutic drug monitoring
• Purpose- To adjust plasma concentration and maintain it within a specified
range.
• Measurement of both values of minimum and maximum concentrations
are to be recorded.
• The necessary dose adjustment is done considering the clearance of drug
to remain constant.
• Applied when-
• The drug has a low therapeutic index
• There is a good plasma concentration- biological response relationship
• There are no other easily measurable physiological parameters
• Or, to monitor adherence or adverse drug reactions

21. Therapeutic drug monitoring
• Sampling of blood is to be done
only after steady state of plasma
concentration is reached, ie, after
five half lives except in case of
toxicity
• After the steady state is reached,
sampling to be done after proper
time for distribution of drug to
finish.
• A therapeutic range of plasma
concentration is used to guide the
desired concentration of drug

22. THANK YOU