Pharmacokinetic concepts and principles in humans in order to design individualized dosage regimens which optimize the therapeutic response of a medication while minimizing the chance of an adverse drug reaction.
.strong correlations between drug concentrations and their pharmacologic responses. digoxin -- myocardium,. So measuring the plasma concentartion is very useful in monitoring efficacy and toxicity. Key factor..
. phenytoin2 and salicylic acid3 follow Michaelis-Menten pharmacokinetics
Now I would like to discuss important pkparamaetr first.. loading dose (LD) dose that is required to achieve a particular steady-state drug concentration immediately after the dose is administered: For example, the reason warfarin has such a small volume of distribution is that it is highly bound to serumalbumin so that the free fraction of drug in the blood (fB) is very small.Digoxin has a very large volume of distribution because it is very highly bound to tissues (primarily muscle)
What is MD, the dose tha administered at regular interval to maintain the staedy state concentartion at therapeutic range e.
Total drug clearance is equal to cl,liver, clkidney, clotherora …. clearance for an organ, such as the liver or kidney, is determined by the blood flow to the organ and ER, ER the ability of the organ to metabolize or eliminate the druggns. which is the fraction of drug removed by the organ, and is computed by measuring the concentrations of the drug entering (Cin) and leaving (Cout) the organ. However, the extraction ratio is determined duringthe drug development process, and knowledge of this parameter useful in determining how the pharmacokinetics of a drug will change if a patient develops hepatic, renal, or cardiac failure.
hepatic clearance (ClH) for a drug is product of liver blood flow and the hepatic extraction ratio(ERH) for the drug (ClH = LBF ⋅ ERH)……….HER is nothing but intrinsic clearance----intrinsic ability of the liver enzyme to metabolize a drug.. most drugs have a large hepatic extraction ratio (ERH ≥ 0.7) or a small hepatic extraction ratio (ERH ≤ 0.3), hepatic clearance is very sensitive to changes in liver blood flow due to congestive heart failure, coartation of arota, cirrosis of liver or liver disease, as results CL decraeses and concentration increases.
Capacity to metabolize drug is very large- mean as soon as drug enter the body ,most of drug metabolized by liver enzyme. So what amount entering the liver is matter, in another way liver blood flow. For low– LBF is not the function CL,
When drugs that follow linear pharmacokinetics are given to humans, and graph plotted time vsconcet initial absorption phase & distribution phase fallowed by elimination phase. Elimination phase of the drug that fellows linear PK is constant.
The half-life, determines the time to steady state concentration when drug administered continuosly. When a drug administered it reaches ssc after 5t12,,, t1/2 = (0.693 ⋅ V)/Cl, ke = Cl/V. clearance and volume of distribution depend solely on physiological parameters and can vary independently of each other, they are known as independent parameters.
When a drug is administered extravascularly, the entire dose may not enter the systemic circulation. For example, an orally administered tablet may not completely dissolve so that part of the dose is eliminated in the stool, or a transdermal patch may not release the entire dose before it is removed from the skin.When drug administered orally drug molecules must pass through several organs before entering the systemic circulation,GIT, portal vein liver, lung, In liver disease- increase Bio……… I s calculated by AUC
When this occurs, steady-state drug serum concentrations increase in a disproportionate manner after a dosage increase.saturable drug metabolism can occur in drug overdose cases where the drug con- centration far exceeds the therapeutic range for the medication
PK of drug changes in disease state and requiredrud dose modification. . Renal or hepatic disease will decrease the elimination or metabolism of the majority drugs and change the clearance of the agent. Dialysis procedures, conducted using artificial kidneys in patients with renal failure, removes some medications from the body… Heart failure results in low cardiac output which decreases blood flow to eliminating organs. Obesity adds excessive adipose tissue to the body which may change the way drugs distribute in the body and alter the volume of distribution for the medication.
the average steady-state concentration is identical for both dosage schemes
To illustrate this point..
Drugs can also be added to peritoneal dialysis fluid. If the agent is absorbed from the dialysis fluid into the body, systemic effects due to the drug may occur. Epoetin and insulin have been administered in this fashion to patients receiving peritoneal dialysis
T half increase
The unbound steady-state concentration of drug in the blood equals the product of the total steady-state concentration and the unbound fraction of drug in theblood: Cssu = fBCss
If the coadministered drug increases liver blood flow, as can be the case with vasodilators like the calcium channel blockers,51,52 all of the aforementioned changes will occur in theopposite direction
Clinical Pharmacokinetics and
Dr Manukumar Shetty
Department of Pharmacology
UCMS & GTB Hospital
• Clinical pharmacokinetics is
pharmacokinetic principles to the safe and effective
therapeutic management of drugs in an individual patient.
• Enhancing efficacy and decreasing toxicity of a patient's drug
• Plasma drug concentrations are affected by the rate at which
drug is administered, the volume in which it distributes, and
• When medications are given on a continuous
basis(theophylline i.v 50mg/hr, oral 300mg/6hr), serum
concentrations increase until the rate of drug administration
equals the elimination rate.
• Steady-state serum or blood concentrations are used to
assess patient response and compute new dosage regimens.
• When doses are increased for most drugs, steady-state
concentrations increase in a proportional fashion leading to
linear pharmacokinetics .
• When steady-state concentrations change in a
disproportionate fashion after the dose is altered, drug is
said to follow nonlinear pharmacokinetics.
• Steady-state concentrations increase more than expected
after a dosage increase, the most likely explanation is that
the processes removing the drug from the body have
• When steady-state concentrations increase less than
expected after a dosage increase, there are two typical
– Saturable plasma protein binding site- valproic acid & disopyramide
– Carbamazepine increase their own rate of metabolism autoinduction
• Drugs that exhibit nonlinear pharmacokinetics are
oftentimes very difficult to dose correctly.
• Drugs that follow linear pharmacokinetics is more
straightforward and relatively easy
Problem no 1
• Two new antibiotics are marketed by a pharmaceutical
manufacture. Reading the package insert, you find the
• What type of pharmacokinetics do each of these drugs
Volume of distribution(Vd)
• Fluid volume that would be required to contain all of the
drug in the body at the same concentration measured in the
blood or plasma:
• Volume of distribution is an important pharmacokinetic
parameter because it determines the loading dose=Css ⋅ V d.
• How the drug binds in the blood or serum compared to the
binding in tissues is also an important determinate of the Vd
for a drug.
• A drug's Vd therefore reflects the extent to which it is
present in extra vascular tissues and not in the plasma,.
Problem no - 02
• If 3 g of a drug are added and distributed throughout a tank
and the resulting concentration is 0.15 g/L, calculate the
volume of the tank.
A. 10 L
B. 20 L
C. 30 L
D. 200 L
Problem no - 03
• If 100 mg of drug X is administered intravenously and the
plasma concentration is determined to be 5 mg/L just after
the dose is given, calculate volume of distribution
Problem no 4
• A physician wants to administer an anesthetic agent
at a rate of 2 mg/hr by IV infusion. The elimination
rate constant is 0.1 hr– 1, and the volume of
distribution (one compartment) is 10 L. What
loading dose should be recommended if the drug
level to reach 2 μg/mL immediately?
Given, infusion rate =2mg/hr
elimination rate = 0.1 hr– 1
volume of distribution =10L
Required concentration = 2 μg/mL
Loading dose = Vd X Css
= 1000mL X 2 μg/mL
= 2000 μg
Here we can calculate LD using infusion rate and elimination rate as well .
• A basic type of model used in pharmacokinetics is the
• Compartmental models are categorized by the number of
compartments needed to describe the drug's behavior in the
• There are one- compartment, two-compartment, and
• The compartments do not represent a specific tissue or fluid
but may represent a group of similar tissues or fluids.
• These models can be used to predict the time course of drug
concentrations in the body
The one compartment
model linear assumes
that the drug in question
is evenly distributed
throughout the body
into a single
This model is only
appropriate for drugs
which rapidly and
between the plasma
and other body tissues.
Drugs which exhibit a
slow equilibration with
peripheral tissues, are
best described with a
• The solid line shows the serum concentration/time graph for
• The dashed line represents the serum concentration/time
plot for a drug that follows two- compartment model
pharmacokinetics after an intravenous bolus is given.
Plasma concentration-time curve fallowing i.v administration of a drug (500mg) to a 70kg pt
• V= dose/Cp
= 500/16= 31.3L
• Cl=kV= 90mL/mim
• V= dose/Cp
• Cl=kV= 84mL/mim
Importance of two-compartment
• For many drugs, multicompartment kinetics may be
observed for significant periods of time.
• Failure to consider the distribution phase can lead to
significant errors in estimates of clearance and in predictions
of the appropriate dosage.
Also, the difference between the "central" distribution
volume is important in deciding a loading dose strategy.
• The definition of clearance is the volume of serum or blood
completely cleared of the drug per unit time.
• Clearance is the most important pharmacokinetic parameter
because it determines the maintenance dose=Cl.Css.
• Theophylline clearance for a patient,3 L/h and the desired
steady-state theophylline serum concentration, 10 µg/mL,
the theophylline maintenance dose to achieve this
concentration would be 30 mg/h.
• The liver is most often the organ responsible for drug
metabolism while kidney is responsible for drug elimination.
• The drug clearance for an organ is equal to the product of
the blood flow to the organ and the extraction ratio of the
• extraction ratio (ER) : The ability of an organ to remove or
extract the drug from the blood or serum
ER = (Cin − Cout)/Cin
• How the pharmacokinetics of a drug will change during a
drug interaction or if a patient develops hepatic, renal, or
• hepatic clearance (ClH) for a drug is product of liver blood
flow and the hepatic extraction ratio (ERH) .
ClH = LBF ⋅ Cl′int
• ERH- intrinsic ability of the enzyme to metabolize a drug
• hepatic clearance is very sensitive to changes in liver blood
flow due to congestive heart failure or liver disease
• high hepatic extraction ratios(ER>70%)
– Capacity to metabolize drug is very large, hepatic
clearance is mainly a function of liver blood flow.
– ClH, does not change much when protein binding
displacement or enzyme induction or inhibition occurs
due to drug interactions.
– lidocaine, morphine, and most TCA.
• low hepatic extraction ratio (ER<30%)
– ClH does not change much when liver blood flow
decreases secondary to liver or cardiac disease.
– valproic acid, Phenytoin, and warfarin.
• The physiological determinants of renal clearance are
glomerular filtration rate (GFR),the free fraction of drug in
the blood or serum (fB), renal tubular secretion (Clsec), and
the fraction of drug reabsorbed in the kidney (FR)
• If the renal clearance of a drug is greater than glomerular
filtration rate, it is likely that the drug was eliminated, in
part, by active tubular secretion.
Problem no - 5
• Verapamil has a hepatic extraction ratio of 90%
(ERH = 0.90) For patients with normal liver blood
flow (LBF = 1.5 L/min) calculate hepatic clearance.
• ClH = LBF ⋅ ERH,
ClH = 1.5 L/min x 0.90
= 1.35 L/min;
• hepatic clearance would be 1.35 L/min
• The time that it takes for serum concentrations to decrease
by 1/2 in the elimination phase is a constant and is called
the half-life (t1/2).
• t1/2 = 0.693/ ke,
• Ke, elimination rate constant = -(ln C1 − ln C2)/(t1 − t2)
The half-life, determines the time to steady state
concentration and the dosage interval.
The half-life is dependent parameters because their
values depend on the clearance (Cl) and volume of distribution
Problem no - 6
• After the first dose of gentamicin is given to a
patient with renal failure, the following serum
concentrations are obtained:
TIME AFTER DOSAGE
• Compute the half-life and the elimination rate
constant for this patient.
• ke =−(ln C1 − ln C2)/(t1 − t2)
= −(ln 7.7 − ln 4)/(1 h − 48 h)
= 0.0139 per hr.
• The elimination rate constant can be used to
calculate the half-life for the patient:
t1/2 = 0.693/ke,
= 0.693/0.0139 h−1
= 50 h
Problem no - 7
• PZ is a 35-year-old, 60-kg female with a Staphylococcus
aureus wound infection. While receiving vancomycin 1 g
every 12 hours (infused over one hour), the steady- state
peak concentration (obtained one-half hour after the end of
infusion) was 35 mg/L, and the steady-state trough
concentration (obtained immediately predose) was 15 mg/L.
so calculate elimination rate and half-life
• Css after one-half hr is 35mg/L & Css obtained
immediately predose is 15mg/L
• Elimination rate , ke =− (ln C1 − ln C2)/(t1 − t2)
=− *35 mg/L − 5 mg/L+ / (1.5 h − 12 h)
= 0.081 per hr
• t1/2 = 0.693/ ke
= 8.6 hr
• The fraction of the administered dose that is delivered to the
systemic circulation is known as the bioavailability for the
• The loss of drug before entering the systemic vascular
system is known as presystemic metabolism or the first-pass
Problem no - 8
• A new immunosuppresant, is being studied in the
renal transplant clinic. Based on previous
studies, the following area under the serum
concentra- tion/time curves (AUC) were measured
after single doses of 10 mg in renal transplant
patients: intravenous bolus AUC = 1530 mg ⋅
h/L, oral capsule AUC = 1220 mg ⋅ h/L, oral liquid
AUC = 1420 mg ⋅ h/L. What is the bioavailability of
the oral capsule and oral liquid? What is the relative
bioavailability of the oral capsule compared to the
• The bioavailability for the capsule and liquid are:
F = AUCPO/AUCIV
for capsule, F = (1220 mg ⋅ h/L)/(1530 mg ⋅ h/L)
= 0.80 or 80%;
for liquid, F = (1420 mg ⋅ h/L)/(1530 mg ⋅ h/L)
= 0.93 or 93%.
• The relative bioavailability is:
Frelative = AUCCAPSULE/ AUCLIQUID;
= (1220 mg ⋅ h/L)/(1420 mg ⋅ h/L)
= 0.86 or 86%
Problem no - 9
• A patient with liver failure need to be treated with
a new antiarrhythmic drug. You find a research
study that contains the following information in
patients similar to the ones you need to treat:
normal subjects: clearance = 45 L/h, volume of
distribution = 175 L; liver failure: clearance = 15 L/h,
volume of distribution = 300 L. calculate
recommend intravenous loading dose (LD) and
continuous intravenous infusion maintenance dose
(MD) to achieve a steady-state concentration of 10
Problem no - 10
• A patient with heart failure need to be treated with
a new antiarrhythmic drug. normal subjects:
clearance = 45 L/h, volume of distribution = 175 L;
heart failure: clearance = 30 L/h, volume of
distribution = 100 L. Recommend an intravenous
loading dose (LD) and continuous intra- venous
infusion maintenance dose (MD) to achieve a
steady-state concentration of 10 µg/mL for patients
based on this data and estimate the time it will take
to achieve steady-state conditions.
Cl = 30 L/h, V = 100 L, Css=10µg/ml
LD = V ⋅ Css, Css= 10µg/mL=10mg/L
LD = (100 L)(10 mg/L) = 1000 mg intravenous bolus;
MD = Cl ⋅ Css, MD = (30 L/h) (10 mg/L) = 300 mg/h
• The half-life would be estimated using the clearance and
volume of distribution
• t1/2 = (0.693 V)/Cl, t1/2 = [(0.693)(100 L)]/ (30 L/h) = 2.3
• Steady state would be achieved in 3–5 t1/2 equal to 7–12
Problem no -11
• An antibiotic has a volume of distribution of 10 L
and a k of 0.2 hr– 1. A steady-state plasma
concentration of 10 μg/mL is desired. Calculate the
infusion rate needed to maintain this concentration.
If patient developed uremic condition and the
elimination rate constant has decreased to 0.1 hr– 1.
calculate infusion rate.
Infusion rate= Css x Vd x k
= 10 μg/mL x 1000ml x 0.2
Uremic condition, K reduced to 0.1 hr– 1
=10 μg/mL x 1000ml x 0.1
When the elimination rate constant decreases, the infusion
rate must decrease proportionately to maintain the same
However, because the elimination rate constant is smaller (ie,
the elimination t 1/2 is longer), the time to reach C SS will be
Problem no – 12*
• An antibiotic has an elimination half-life of 3–6
hours in the general population. A patient was
given an IV infusion of an antibiotic at an infusion
rate of 15 mg/hr. Blood samples were taken at 8
and at 24 hours and plasma drug concentrations
were 5.5 and 6.5 mg/L, respectively, If the desired
therapeutic plasma concentration is 8 mg/L for the
above patient (), what is a suitable infusion rate for
• Because the second plasma sample was taken at 24 hours, or
24/6 = 4 half-lives after infusion, the plasma drug
concentration in this sample is approaching 95%, (Css)
We know MD= Css x Cl
The new infusion rate should be
MD= Css X Cl
= 8 X 2.31
• This is the type of non- linear pharmacokinetics that occurs
when the number of drug molecules saturates the enzyme’s
ability to metabolize the drug.
• Clearance of a drug is not a constant & it is concentration
dependent. As the dose or concentration increases, the
clearance rate (Cl) decreases and half-life becomes longer for
• This situation is also known as zero-order pharmacokinetic
• Drugs that exhibit nonlinear pharmacokinetics are very
difficult to dose correctly.
Drug dosing in special populations
• In patients with renal disease, there is a functional loss of
• The method recommended by FDA to estimate renal
function for the purposes of drug dosing is to measure
creatinine clearance .
• The most widely used method to estimate creatinine
clearance , is by Cockcroft and Gault formula.
• FDA, required pharmacokinetic studies & package insert for
initial dosage guidelines to be done before receiving agency
Problem no - 13
• A 52-year-old, 65-kg, 5-ft 3-in tall female patient
with a methicillin-resistant Staphylococcus aureus
(MRSA) infection needs to have an initial
vancomycin dose computed. In order to do this, an
estimated creatinine clearance needs to be
calculated. The patient has a serum creatinine value
equal to 1.8 mg/dL. Calculate this patient’s
estimated creatinine clearance and estimated
vancomycin clearance [assume vancomycin
clearance is Cl (in mL/min/kg) = 0.695 (CrCl in
mL/min/kg) + 0.05].
Problem no - 14
• A 70-year-old, 80-kg, 5-ft 11-in tall male with a
Pseudomonas aeruginosa infection needs to have
an initial tobramycin dose computed. In order to do
this, an estimated creatinine clearance must be
calculated. The patient’s current serum creatinine
equals 2.5 mg/dL and is stable. Compute this
patient’s estimated creatinine clearance and
estimated tobramycin elimination rate constant and
half-life [assume tobramycin elimination rate
constant is ke (in h−1) = 0.00293 (CrCl in mL/min) +
• Modify doses for patients with renal impairment
– Decrease the drug dose and retain the usual dosage interval,
– Retain the usual dose and increase the dosage interval, or
– Simultaneously decrease the dosage and prolong the dosage interval
• In a renal failure patient & receiving dialysis, clearance is
from nonrenal routes and dialysis (Cl = ClNR + ClD)
• It is important to understand when drug dosing needs to be
modified in renal failure patients undergoing dialysis.
• Drug Characteristics that Effect Dialysis Removal
1. Molecular size :- Molecular size relative to pore size in the
semipermeable membrane, low-flux/high-flux artificial kidneys
2. Water/lipid solubility
3. Plasma protein binding :- Only unbound drug molecules are
able to pass through the pores in the semipermeable membrane
4. Volume of distribution
V = VB + (fB/fT)VT
Agents with large volumes of distribution are not easily
removed from the body
(aminoglycoside, theophylline) usually high dialysis clearance
tobramycin in a
Problem no - 15
• A patient receiving hemodialysis has the following
concentrations obtained during a hemodialysis run:
concentration into artificial kidney = 75 mg/L,
concentration leaving artificial kidney = 25 mg/L.
Blood flow through the artificial kidney is 400
mL/min. Compute the hemodialysis extraction ratio
Problem no - 16
• A 47-year-old, 75-kg, male hemodialysis patient with chronic
renal failure has a serious gram-negative infection being
treated with a new antibiotic. The following concentrations
were obtained: Monday, 1200 H (post-hemodialysis) = 15
mg/L, Monday, 1205 H (post-IV bolus 1000 mg dose) = 65
mg/L, Wednesday, 0800 H (pre-hemodialysis) = 32 mg/L,
Wednesday, 1200 H (post-hemodialysis for 4 hours) = 8
mg/L. Compute volume of distribution, elimination rate
constant, and half-life for the interdialysis period, and the
hemodialysis extraction ratio. What post-hemodialysis dose
on Wednesday would achieve a postdose concentration of
• Compared to hemodialysis, pd
removes drug much less
• less likely require replacement
• Drug dosages need to be
increased while patients receive
• T1/2 aminoglycoside
– end-stage renal disease~50 hours.
– During haemodialysis ~4 hours,
– during pd ~36 hours
Hepatocyte damage/permanent loss of functional
hepatocytes, Liver blood flow decreases, increase in free
fraction of drugs( ~increase Vd)
Reduces the hepatic clearance of the drug
A simultaneous decrease in liver first-pass effect results in
extremely large increases in steady-state concentrations for
orally administered drugs.
• Child-Pugh Scores
• The Child-Pugh score consists of five laboratory tests or
clinical symptoms. The five areas are serum albumin, total
bilirubin, prothrombin time, ascites, and hepatic
• A Child-Pugh score equal to 8–9- decrease (~25%) in initial
daily drug dose
• A score of 10 or greater indicates that a significant decrease
in initial daily dose (~ 50%) is required for drugs that are
mostly liver metabolized
• for a drug with a low hepatic extraction ratio
• For a drug with a high hepatic extraction ratio
Effect of physiologic, pharmacokinetic, and drug effect
parameters when low hepatic extraction ratio drug is given to
a patient as a continuous intravenous infusion, acute hepatitis
a high hepatic extraction ratio drug if
liver blood flow decreases
• The presence of excessive adipose tissue can alter the
pharmacokinetics of drugs by changing the volume of
• High lipid solubility drugs tend to partition into adipose
tissue, & Vd is dramatically larger than in norma.(diazepam,
carbamazepine, and trazodone)
• If the Vd for a hydrophilic drug is small, the additional
extracellular fluid contained in adipose tissue may
significantly alter the distribution of the agent.aminoglycoside
• obese individuals, increased GFR. thus increase the renal
• Half-life = (0.693 ⋅ V)/Cl.
• Aminoglycoside antibiotics, CL & Vd increases of same
magnitude in obese patients, so half-life does not change.
• If the Vd increases with obesity, but Cl is unaffected, half-life
can increase dramatically as with carbamazepine.
• Finally, if Cl changes and Vd remains constant, obesity may
also cause a change in the half-life of a drug as is the case for
Pharmacokinetic drug interactions occur between drugs when one
agent changes the Cl or Vd of another medication.
Enzyme inhibition decreases intrinsic clearance, and enzyme induction
increases intrinsic clearance.
Two drugs eliminated by the same active renal tubular secretion
mechanism can compete for the pathway and decrease the renal
clearance of one or both agents
Changes in plasma protein binding also cause alterations in volume of
Plasma Protein Binding Displacement
• Drug with a low hepatic extraction ratio
– plasma protein binding displacing compound will increase clearance
(↑Cl =↑fBCl′int) and volume of distribution *↑V = VB + (↑fB/fT)VT]
– The pharmacologic effect of the drug does not change because the
free concentration of drug in the blood is unchanged.
• For drugs with high hepatic extraction ratios
– clearance does not change. However, both Vd and half-life *↑t1/2 =
(0.693 ⋅↑V)/ Cl] will increase because of plasma protein binding
displacement of the drug
– pharmacologic effect (↑effect ∝↑Cssu) of the drug will both
Alteration in Organ Blood Flow
β-blockers can decrease heart rate and
cardiac output which decreases liver
Decrease clearance for high hepatic
extraction ratio drugs (lidocaine).
Vd remains unaltered, the half-life
increase, total steady-state drug
concentrations will increase