Pharmacokinetic parameters

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 ( V d ) 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 ( V d ) owing to its high plasma protein binding while Chloroquine has high ( V d ) 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 (C A ) and concentration of 10mg/ml in hepatic vein (C V ). Then, hepatic extraction ratio will be- C A - C V / C A = 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 ( K e ) Fraction of drug that is excreted from the body per unit time Rate of elimination = K e X Concentration of drug in plasma Thus, K e = Clearance/Volume of distribution The relationship between concentration at a time t (C) after administering the drug and the steady state concentration ( C ss ) 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 (t 1/2 ) 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 ( Δ C) 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

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