Pharmacokinetic variability disease

AMRUTHA JOSE
PHARMACY PRACTICE
NEHRU COLLEGE

“Inter-individual variations of a drugs pharmacokinetic
parameters, resulting in fairly different plasma
concentration-time profiles after administration of the
same dose to different patients.”
PHARMACOKINETIC VARIABILITY

Pharmacokinetic variability which is due to difference in
drug concentration at the site of action(as reflected from
plasma drug concentration) because of inter individual
differences in the drug.
Absorption, Distribution, Metabolism and Excretion.

Pharmacokinetic variability is greater in sick people than
in healthy people.
Disease affects various organs systems of the body and
affects the way drugs are absorbed ,distributed, excreted and
metabolized.
RENAL DISEASE: affect drug excretion and drug binding.
CVD: affect the transport of drugs to eliminating organs
such as the liver and the kidney.
HEPATIC DISEASE: affects drug metabolism.

Renal Diseases Drugs which are predominantly cleared via
the kidney will accumulate to higher drug concentrations in
the plasma of patients with poor renal perfusion(congestive
heart failure, shock, and trauma) or with intrinsic renal
diseases(acute renal failure, chronic renal failure) than in
normal subjects. In the presence of renal diseases some
metabolic functions seem to be impaired.

•It is the volume of blood plasma that is cleared of
creatinine per unit time.
•The most common way of assessing renal function.
•Creatinine is poorly secreted and not subjected to tubular
reabsorption.
•It is useful to measure GFR and it tells about only one
aspect of renal function(i.e.,filtration).
•It is an excellent indicator of the severity of renal disease.

• it is by determing renal clearance of creatinine (the
endogenous end product of muscle metabolism )and
comparing this value to that observed in individuals of
comparable size,sex and age with normal renal function.
•Creatine clearance may be measured directly or indirectly
from serum levels of creatinine.

Direct measurement of creatinine clearance is made by
determining the amount of endogenous creatinine excreted
in urine over a 24-hr period and the creatine concentration
in the plasma during this period.
Usually, blood samples are taken for creatinine
determination immediately before and at the end of the
urine collection period.

Creatinine clearance
Normal value: 100-125ml/min for 1.73m 2 body
surface area
 Moderate renal failure: 20-50ml/min
 Severe renal failure : less than 10ml/min creatinine
clearance
Clcr = Rate of urinary excretion of creatinine
Average serum creatinine concentration

COCKCROFT AND GAULT METHOD:
According to this method creatinine clearance can be
calculated by following formulas.
Limitations: Should be used in adults aged 18 years and
older.
For males: Crcl ={(140-age)BW}/(72*Scr)
For females: Crcl ={0.85(140-age)BW}/(72*Scr)

DRUG EXCRETION
Linear relationship between the renal clearance of drug
and creatinine clearance in patients with varying degrees
of renal function.
A= Drug specific constant
e.g.-For nadolol A is equal to about 0.6.
RENAL CLEARANCE = A * Creatinine clearance

FIG .A
Relationship between the renal clearance of nadalol ,a
β blocker ,and creatinine clearance in patients with
varying degree of renal function.

Urinary excretion of nadolol after a single 80-mg oral dose
in patients with varying degrees of renal function.
Amount of nadalol excreted decreases with decreasing
renal function.

DRUG ELIMINATION
The effect of renal disease on the elimination of drug
depends on the renal status of the patient and the
elimination characteristics of the drug.

Fig -B
• Renal disease has the largest effect on drug A and the
smallest effect on drug C.
• Drug A,B,& C are 90%,50%and 10% eliminated by renal
excretion in patients with normal renal function.
• It is assumed that the non renal clearance of these drugs is
unaffected by kidney disease and that renal clearance is
linearly related to creatinine clearance.
• Under these conditions the total clearance of the drug
from blood plasma is also a linear function of creatinine
clearence.

TOTAL CLEARANCE = A*CREATININE CLEARENCE +
NONRENAL CLEARANCE
FIG –B also shows how different the effect of renal
impairment can be on the total clearance and half life of
different drugs . At a creatinine clearance of 20 ml/min
per 1.73m2,the total clearance of drug A is decreased by
75%,that of drug B by 42% and that of drug c by only 8.5%.

EXAMPLES FOR DRUG A
Cephalosoprin,penicillin,andaminoglycoside
antibiotics,ethambutol,flucytosine,vancomycin,lithium,and
most diuretics(more than 80% excreted un changed.)
EXAMPLES FOR DRUG B
Digoxin, nadolol, and cimetidine (40-75%excreted
unchanged)

RENAL IMPAIRMENT
The kidney is an important organ in regulating body
fluids, removal of metabolic waste, electrolyte balance and
drug excretion from the body Impairment (or)
degeneration of kidney function affects the
pharmacokinetics of the drugs. some of the common
causes for kidney failure include disease, injury,and drug
intoxication.

EFFECT OF RENAL DISEASE ON DRUG
ABSORPTION..Downloadsrenal.pdf
Effect of renal disease on drug absorption Impaired renal
function will result in increased bioavailability of drugs
exhibiting first-pass metabolism when the function of drug
metabolizing enzymes is compromised.

EFFECT OF RENAL DISEASE ON DRUG DISTRIBUTION
o Impaired renal function is associated with important
changes in the binding of drugs to plasma proteins.
o Protein binding in serum from uremic patients is
decreased.
o Most acidic drugs bind to the bilirubin site on albumin.
The reduced binding occurs when renal function is impaired
for the following reasons.
 Reduction in serum albumin concentration.
 Structural changes in binding. sites.
 Displacement of drug from albumin binding sites by
organic molecules that accumulate in uremia.

The volume of distribution of a drug can decrease if
compounds normally excreted by the kidney
accumulate to the extent that displacement of drug
from tissue binding sites occurs.

The relationship between drug binding and volume of
distribution is given by following equation.
V = VB + (f B VT/f T)
Where
V= apparent volume of distribution
VB = blood volume
VT = extravascular volume
f B =free (unbound) fractions of drug in the blood
f T = free (unbound) fractions of drug in the
extravascular(tissue) spaces

The effect of plasma protein binding on drug clearance is less
direct .The clearance (Cl) of drug eliminated solely by hepatic
metabolism is given by following equation.
Cl= HBF f B Cli
HBF + f B Cli
HBF= Hepatic blood flow rate
f B = fraction free in the blood
Cli = intrinsic clearance

METABOLISM
 Most drugs are not excreted by the kidneys unchanged
but are bio transformed to metabolites that are then
excreted.
 Renal failure retard the excretion of metabolites.
 Renal failure alters the metabolic clearance of the drug.
 The impact of impaired renal function on drug
metabolism is dependent on the metabolic pathway.

ELIMINATION
The effect of renal disease on the elimination of a drug
depends on the renal status of the patient and the elimination
characteristics of the drug.
For many drugs CL E consists of renal(CL R ) and non
renal(CL NR ) components.
Non renal excretion includes Biliary excretion, Pulmonary
excretion ,salivary excretion etc..
CL E = CL R + CL NR

Generally, one should consider a possible, modest
decrease in drug doses when creatinine clearance is <50-
60mL/min.
A moderate decrease in drug doses when creatinine
clearance is < 25-30 mL/min.
A substantial decrease in drug doses when creatinine
clearance is <15mL/min.

DOSE ADJUSTMENT IN RENAL DISEASE
• In the renal disease, the renal clearance and
elimination rate are reduced, the elimination half-life is
increased and the volume of distribution is altered.
• The half- lives of some drugs are changed sufficiently
in patients with impaired renal function to warrant
change in the usual dosage regimen to prevent
accumulation of the drug in the body to toxic levels.
• Changes in regimen usually take the form of reducing
the dose per dosing interval .

EXAMPLES -01
• Cephalexin is administered as a 250mg to 1g dose every
4 to 6 hr. Its average half life in patients with normal
renal function is about 0.5 to 1hr.
• In patient with a creatinine clearance of 10-15ml/min
,the half life of the drug is increased about 8 fold
,because cephalexin is eliminated almost solely by
urinary excretion.
• The dosing frequency suggested for the patient with this
degree of renal impairment is the usual dose every
24hr,a dosing interval 4-6times longer than usual.

EXAMPLE – 02
• The average half –life of digoxin is 1.6days in
patients with normal renal function
• But is increased to 4.4days in a nephric patients.
• The usual daily maintenance dose of digoxin
ranges from 125-500µg.
• The daily maintenance dose of digoxin in patients
with little or renal function, however should be
only one third to one half that used in patients
with normal renal function.

EXAMPLE-03
Rodvolt et al studied the kinetics of iv vancomycin in adult
patients with various degrees of renal function, who were
receiving the drug for treatment of gram positive infections
.Patients were categorized into three groups based on
measured creatinine clearance : ˃70,40 to 70 and 10 to 39
ml/min per 1.73m
Vancomycin clearance decreased in a predictable manner,
averaging 98ml/min 1.73m2 in group 1 ,53 in group 2,and
31 in group 3.

On the basis of these results, Rodvolt et al developed dosage
guidelines. They accomplished this by decreasing the daily
dose while extending the dosing interval. They proposed the
following algorithm for daily dose.
Daily Dose (mg/kg)=0.227CrCl + 5.67
Where CrCl is expressed as ml/min per 70kg.Practical
dosing intervals ranged from every 8hr to 48hr,based on
renal function. The investigators suggested that vancomycin
is to be given 3 times a day in patients with CrCl ˃ml/min
per70kg, once a day in patients with CrCl values of 20-39
and every other day in patients with CrCl values of 10-19.

Liver metabolism is the major route for elimination for a
wide variety of drugs & it can be affected by a variety of
parameters.
Hepatic drug clearance can be defined as the volume of
blood per fusing the liver that is cleared of the drug per unit
of time. There are three major parameters that determine
drug elimination by the liver:
1.blood flow through the liver (Q), which reflects drug
delivery to the liver the fraction of

2.drug in the blood that is free or not bound to plasma
proteins and capable of interacting with hepatic enzymes
(f)
3.the intrinsic ability of hepatic enzymes to metabolize the
drug, which is commonly referred to as “intrinsic
clearance” (Clint). Intrinsic clearance is the ability of the
liver to remove drug in the absence of flow limitations
and binding to cells or proteins in blood.

The ratio of the hepatic clearance of a drug to the hepatic
blood flow is called the extraction ratio of the drug.
Extraction ratio can be generally classified as high (>0.7),
intermediate (0.3-0.7) or low (<0.3) according to the
fraction of drug removed during one pass through the
liver.

Rowland's Equation
Hepatic Clearance: Cl(h) = Q [(f x Clint)/(Q+ f x Clint)]
Q = hepatic blood flow
f = fraction of free drug (not bound)
Clint = intrinsic capacity of the hepatocytes to metabolize
a drug
Hepatic Clearance: Cl(h) = Q [(f x Clint)/(Q+ f x
Clint)]

ANTIPYRINE
Antipyrine has been used widely as a model drug to
investigate the effects of liver disease on drug metabolism in
man.
In general, the half life of antipyrine was prolonged in
these patients compared to that found in healthy subjects.
Patients with chronic liver disease, however ,showed a
greater increase in half life than those with acute ,reversible
conditions.
Compared to healthy subjects who had an average half life
of 12hr ,patients with cirrhosis and chronic active hepatitis
had average antipyrine half lives of 34hr and 26hr,
respectively.

DRUG CATEGORIES
High extraction ratio:. These drugs are rapidly and
extensively cleared from the blood by the liver (e.g. in a
single pass). Their clearance depends primarily on hepatic
blood flow, and binding to blood components is not an
obstacle for extraction; the extraction is said to be non-
restrictive or blood flow dependent. When this is the case in
Rowlands equation: f x Clint is »Q and the equation can be
simplified to Cl(h) = Q.

Low extraction ratio.: These drugs are not efficiently cleared
by the liver and are extracted less avidly and incompletely
from hepatic blood. Their clearance is relatively independent
of hepatic blood flow, and is primarily determined by the
intrinsic metabolizing capacity of the liver and by the free
drug fraction. The extraction is said to
be restrictive or capacity limited. When this is the case f x
Clint is «Q and Rowland's equation can be simplified to Cl(h) =
f x Clint. An increase in the fraction of unbound drug (f) will
increase clearance, and a decrease in unbound drug will
decrease clearance.

Total drug concentration at steady state(CSS)is given by
the equation
CSS = k o/Cl
Where ko is dosing rate(mg/min,mg/hr or mg/day) and Cl
is drug clearance.Free drug concentration (CFSS) is the
product of free fraction in the blood and total drug
concentration. Therefore
CFSS = f B ko/Cl
For drugs with low hepatic extraction ratios, eliminated
solely by hepatic metabolism,clearance is given by
CFSS = f B ko/f B Cli = ko / Cli
Total drug concentration at steady state(CSS)is given by
the equation
CSS = k o/Cl
Where ko is dosing rate(mg/min,mg/hr or mg/day) and Cl
is drug clearance.Free drug concentration (CFSS) is the
product of free fraction in the blood and total drug
concentration. Therefore
CFSS = f B ko/Cl
For drugs with low hepatic extraction ratios, eliminated
solely by hepatic metabolism, clearance is given by
CFSS = f B ko/f B Cli = ko / Cli

Intermediate extraction ratio. :Hepatic clearance of these
drugs is dependent on both hepatic blood flow, intrinsic
metabolizing capacity of the liver and the free drug
fraction.

Drugs with "Flow Dependent" hepatic clearance (high
hepatic extraction ratio)
• morphine
• lidocaine
• verapamil
• propranolol
• Nitroglycerin
Pharmacokinetics:
This class of drugs will:
undergo extensive “first pass” metabolism when given orally.
have a hepatic drug clearance that is sensitive to changes in
liver blood flow & less sensitive to alterations in binding to

plasma proteins or “intrinsic clearance” (changes in hepatic
metabolism or biliary excretion).
conditions that reduce hepatic blood flow (CHF, hypotension)
will reduce hepatic clearance

Drugs with "Capacity-Limited" hepatic clearance (low
hepatic extraction ratio)
Warfarin
phenytoin
Pharmacokinetics:
This class of drugs will -
•Have a hepatic clearance that is sensitive to changes in
binding to plasma proteins or changes in drug
metabolism/excretion.
•Have a clearance that is insensitive to changes in liver blood
flow.
•No first “pass metabolism” when given orally.

EXAMPLE-01
•Plasma level of cimetidine after oral administration tended
to be higher in patients with cirrhosis than in control
patients.
•The time after a single oral dose during which plasama
levels exceeded 0.5mg/L was 205 min in controls and 295
min in cirrhotics.
•Clinically, liver disease would seem to require reduction of
cimetidine dose only in the elderly or severely sick patient.

Drugs with intermediate hepatic extraction
aspirin
quinidine
codeine
nortryptyline
Pharmacokinetics:
This class of drugs will:
have a hepatic clearance that is sensitive to changes in
both hepatic blood flow, binding to plasma proteins or
changes in drug metabolism/excretion

• Biopharamaceutics and Clinical pharmacokinetics by
Milo Gibaldi
• Rowland M, Tozer TN (1995). Clinical Pharmacokinetics
• http://tmedweb.tulane.edu/pharmwiki/doku.php/hepatic_
drug_clearance

Pharmacokinetic variability disease

Pharmacokinetic variability disease

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