1. Clinical Pharmacokinetics
University of Nizwa
College of Pharmacy and Nursing
School of Pharmacy
Clinical Pharmacokinetics
PHCY 350
Lecture-3 Basic Parameters of Clinical Pharmacokinetics Dr. Sabin Thomas, M. Pharm. Ph. D. Assistant Professor in Pharmacy Practice School of Pharmacy University of Nizwa

2. Course Outcome
Upon completion of this lecture the students will be able to
differentiate dependent and independent parameters of clinical pharmacokinetics,
calculate extraction ratio, organ clearance and its clinical correlate
differentiate between whole blood, plasma, and serum

3. Pharmacokinetic Parameters are characteristic for disposition and uptake of drug into the body of one specific drug in a specific patient.
The most important parameters are clearance (CL), volume of distribution (V), and Bioavailability (F).
CL is reflective for the drug-eliminating capacity of the body, especially liver and kidneys.
V refers to the distribution of drug within the body including uptake into specific organs and tissues as well as binding to proteins and other macromolecules.
Based on these underlying physiologic process, CL and V are independent of each other and are called primary pharmacokinetic parameters.
Bioavailability (F) refers to the extent of drug uptake into the systemic circulation.

4. Clearance Quantifies the elimination of a drug.
Plasma drug concentrations are affected by
rate at which drug is administered
volume in which it distributes
its clearance
A drug's clearance and the volume of distribution determine its half-life.
Clearance (expressed as volume/time) describes the removal of drug from a volume of plasma in a given unit of time (drug loss from the body).
Clearance does not indicate the amount of drug being removed.

5. It indicates the volume of plasma (or blood) from which the drug is completely removed, or cleared of, in a given time period.
The definition of clearance is the volume of serum or blood completely cleared of the drug per unit time.
Thus, the dimension of clearance is volume per unit time, such as Liters/hour or milliliters/min.

6. Two ways of thinking about drug clearance
the amount of drug (the number of dots) decreases but fills the same volume, resulting in a lower concentration.
Initial Concentration
Resulting Concentration
Elimination over time
to calculate the volume that would be drug-free if the concentration were held constant.
Initial Concentration
Resulting Concentration
Elimination over time
Volume from which the drug is removed over time

7. Clt = Clr + Clm + Clb + Clother
Drugs can be cleared from the body by many different mechanisms, pathways, or organs, including hepatic biotransformation and renal and biliary excretion.
Total body clearance of a drug is the sum of all the clearances by various mechanisms.
Clt = Clr + Clm + Clb + Clother
where
Clt = total body clearance (from all mechanisms, where t refers to total);
Clr = renal clearance (through renal excretion);
Clm = clearance by liver metabolism or biotransformation;
Clb = biliary clearance (through biliary excretion); and
Clother = clearance by all other routes (gastrointestinal tract, pulmonary, etc.).

8. Blood flow through the organ is referred to as Q (mL/minute).
where Cin is the drug concentration in the blood entering the organ and Cout is the drug concentration in the exiting blood.
If the organ eliminates some of the drug, Cin is greater than Cout.
We can measure an organ's ability to remove a drug by relating Cin and Cout. This extraction ratio (E) is
E = Cin - Cout
Cin
This ratio must be a fraction between zero and one.
Organs that are very efficient at eliminating a drug will have an extraction ratio approaching one (i.e., 100% extraction).

9. Rating of Extraction Ratios
Extraction Ratio (E)
Rating
>0.7
High
0.3 – 0.7
Intermediate
<0.3
Low
The drug clearance of any organ is determined by blood flow and the extraction ratio:
Organ clearance = blood flow X extraction ratio
CL organ =Q x Cin - Cout or CL organ =Q x E
Cin
If an organ is very efficient in removing drug (i.e., extraction ratio near one) but blood flow is low, clearance will also be low.
Also, if an organ is inefficient in removing drug (i.e., extraction ratio close to zero) even if blood flow is high, clearance would again be low

10. Clearance is the most important pharmacokinetic parameter because it determines the maintenance dose (MD) that is required to obtain a given steady-state serum concentration (Css).
MD = Css ⋅ Cl.
If one knows the clearance of a drug, and wants to achieve a certain steady-state serum concentration, it is easy to compute the required maintenance dose.
The clearance for an organ, such as the liver or kidney, that metabolizes or eliminates drugs is determined by the blood flow to the organ and the ability of the organ to metabolize or eliminate the drug.

11. Eg. The therapeutic range for theophylline is generally accepted as 10–20 μg/mL for the treatment of asthma with concentrations of 8–12μg/mL considered as a reasonable starting point.
If it were known that the theophylline clearance for a patient equaled 3 L/h and the desired steady-state theophylline serum concentration was 10 μg/mL, the theophylline maintenance dose to achieve this concentration would be 30 mg/h.
10 μg/mL = 10 mg/L
(covert microgram per milliliter to milligram per liter)
Maintenance Dose (MD) = Css x Cl
Css (steady state concentration) = 10 mg/L,
Cl (Clearance) = 3 L/h
MD = 10 mg/L x 3 L/h = 30 mg/h
The total clearance (Cl) for a drug that is metabolized by the liver (Cl H) and eliminated by the kidney (Cl R) is the sum of hepatic and renal clearance for the agent:
Cl = Cl H + Cl R

12. Clinical Correlate
Blood flow and the extraction ratio will determine a drug's clearance.
Propranolol is a drug that is eliminated exclusively by hepatic metabolism.
The extraction ratio for propranolol is greater than 0.9, so most of the drug presented to the liver is removed by one pass through the liver.
Therefore, clearance is approximately equal to liver blood flow (Cl = Q ´ E: when E ~ 1.0, Cl ~ Q).

13. Volume of Distribution
An important parameter for determining proper drug dosing regimens (apparent volume of distribution).
Dosing is proportional to the volume of distribution.
For example: the larger the volume of distribution, the larger a dose must be to achieve a desired target concentration.
To understand how distribution occurs, a basic understanding of body fluids and tissues are needed.

14. The fluid portion (water) in an adult makes up approximately 60% of total body weight and is composed of
intracellular fluid (35%)
extracellular fluid (25%)
Extracellular fluid is made up of plasma (4%) and interstitial fluid (21%).
Interstitial fluid surrounds cells outside the vascular system.
These percentages vary somewhat in a child.

15. Fluid Distribution in Adult
Interstitial Fluid (21%)
Interstitial Fluid (21%)
Extracellular Fluid (25%)
Total Body Weight (100%)
Plasma (4%)
Total Body Water (60%)
Intracellular Fluid (35%)

16. If a drug has a volume of distribution of approximately 15-18L in a 70-kg person, its distribution is limited to extracellular fluid, as that is the approximate volume of extracellular fluid in the body.
If a drug has a volume of distribution of about 40 L, the drug may be distributing into all body water, because a 70-kg person has approximately 40 L of body water (70 kg ´ 60%).
If the volume of distribution is much greater than L, the drug probably is being concentrated in tissue outside the plasma and interstitial fluid.

17. It is also important to distinguish among blood, plasma, and serum.
Blood refers to the fluid portion in combination with formed elements (white cells, red cells, and platelets).
Plasma refers only to the fluid portion of blood (including soluble proteins but not formed elements).
When the soluble protein fibrinogen is removed from plasma, the remaining product is Serum.
Plasma concentration of a drug may be much less than the whole blood concentration if the drug is preferentially sequestered (removed) by red blood cells.

18. Relationship of whole blood, plasma, and serum
(Soluble proteins)
Serum
Fibrinogen (Soluble protein) Removed
Whole Blood
Formed Elements
(RBC,WBC, Platelets)

19. VOLUME OF DISTRIBUTION
It determines the loading dose (LD) that is required to achieve a particular steady-state drug concentration immediately after the dose is administered (high enough to attain the pharmacological effect):
LD = Css ⋅ V
An average volume of distribution measured in other patients with similar demographics (age, weight, gender, etc.) and medical conditions (renal failure, liver failure, heart failure, etc.) is used to estimate a loading dose.

20. The dimension of volume of distribution is in volume units, such as Liters or milliliter.
If the minimum concentration needed to exert the pharmacological effect of the drug is 5 mg/L, one patient will receive a benefit from the drug while the other will have a subtherapeutic concentration.
The concentration achieved in plasma after distribution depends on the dose and the extent of distribution.

21. The ideal loading dose is given as an intravenous bolus dose followed by a continuous intravenous infusion (solid line starting at 16 mg/L) so steady state is achieved immediately and maintained.
If a loading dose was not given and a continuous infusion started (dashed line starting at 0 mg/L), it would take time to reach steady-state concentrations, and the patient may not experience an effect from the drug until a minimum effect concentration is achieved.

22. This is not acceptable for many clinical situations where a quick onset of action is needed.
When this is done, the patient’s volume of distribution may be smaller than average and result in higher than expected concentrations (solid line starting at 30 mg/L) or larger than average and result in lower than expected concentrations (dotted line starting at 7 mg/L).

23. Once drug has entered the vascular system, it becomes distributed throughout the various tissues and body fluids.
For most drugs, distribution throughout the body is not instantaneous, but a time consuming process.
Thus the initial drug distribution volume after intravenous (IV) bolus administration is frequently smaller.
The physiologic determinates of volume of distribution are the actual volume of blood (VB ) and size (measured as a volume) of the various tissues and organs of the body (VT ).
Therefore, a larger person, such as a 160-kg football player, would be expected to have a larger volume of distribution for a drug than a smaller person, such as a 40-kg grandmother.

24. Clinical Correlate
Most drug concentrations are measured using plasma or serum that usually generate similar values.
It is more relevant to use plasma or serum than whole blood measurements to estimate drug concentrations at the site of effect.
However, some drugs such as antimalarials are extensively taken up by red blood cells.
In these situations, whole blood concentrations would be more relevant, although they are not commonly used in clinical practice.

25. Dependent Parameters
The half-life and elimination rate constant are known as dependent parameters because their values depend on the clearance (Cl) and volume of distribution (V) of the agent:
Half Life (t ½) = (0.693 ⋅ V)/Cl,
Elimination rate constant (k e) = Cl/V.
The time taken for serum concentrations to decrease by 1/2 in the elimination phase is a constant and is called the half-life
(t 1/2).
The half-life describes how quickly drug serum concentrations decrease in a patient after a medication is administered, and the dimension of half-life is time (hour, minute, day, etc.).

26. Because the values for clearance and volume of distribution depend solely on physiological parameters and can vary independently of each other, they are known as independent parameters.
Another common measurement used to denote how quickly drug serum concentrations decline in a patient is the elimination rate constant (k e ).
The dimension for the elimination rate constant is reciprocal time (hour−1 , minute−1 , day−1 , etc.)

27. The dosage interval for a drug is determined by the half-life of the agent.
In this case, the half-life of the drug is 8 hours, and the therapeutic range of the drug is 10–20 mg/L.
In order to ensure that maximum serum concentrations never go above and minimum serum concentrations never go below the therapeutic range, it is necessary to give the drug every 8 hours (τ = dosage interval).

28. Elimination rate =AB x Ke
If the amount of drug in body is known, the elimination rate for the drug can be calculated by
Elimination rate =AB x Ke
Where, Ke = elimination rate constant, AB= amount of drug in body
The half life and elimination rate are related to each other by equation,
Half Life (t ½)=0.693/Ke
(or ln2/Ke) ln=0.693
Where, Ke = elimination rate constant

29. The half life is important because it determines the time to steady state during the continuous dosing of a drug and the dosage interval.
If a drug is administered on a continuous basis for 3 half-lives, serum concentrations achieve 90% of steady state values;
On a continuous basis for 5 half-lives, serum concentrations achieve 99% of steady state values;
Or continuous basis for 7 half-lives, serum concentrations achieve 99% of steady state values.
Hence drug serum measures used for pharmacokinetic monitoring can be safely measured after 3 to 5 estimated half lives.