PHARMACOKINETIC VARIABILITY presented by :

Santosh Singh

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.

The major causes of inter subject pharmacokinetic variability are :-

Body weightAge

1.Drug metabolism in new born 2.Plasma protein bonding in new

born 3.Renal excretion in new born 4.Drug metabolism in children PregnancyDisease

BODY WEIGHT :• Administration of the same dose of

the drug to patient with different body weight may produce different drug plasma concentration .

• The dose adjustment base on body weight can decrease in variability in drug concentration between individuals extremely thin or obese on lean body weight may be necessary to decrease variability in drug concentration.

AGE

o Age itself, rather than body size and composition, also affects the distribution and elimination of many drugs.

o Drug binding, metabolism, and excretion may change as a function of age.

o The study panel was divided into 5 groups:

Newborns (2 to 3 days) Infants (1 to 12 months)

Children (4 to 9 years) Adults (16 to 37 years) Elderly subjects (more than 70 years)

oComprehensive examination of the effect of age on drug elimination has been reported for ceftriaxone.

oClearance increased from 0.9 to 2.5 ml/min. when comparing patient 1 to 8 days old with patient 9 to 30 days old.

oThe mean clearance of ceftriaxone in children ranging in age from 1 to 12 months and from 1 to 6 years was 6.2 ml/min. and 9.1 ml/min. respectively.

oThe 18 to 49 years old age group had the highest clearance of ceftriaxone, 17 ml/min.

oOlder groups of patient had progressively lower value of clearance.

oVery elderly patients 75 to 92 years of age had an average clearance of about 8 ml/min.

DRUG METABOLISM IN NEWBORN:

oThe most dramatic age-related differences in drug elimination often occur between the newborn and adult.

oMost of the enzymatic microsomal systems required for drug metabolism are present at birth, but their concentration are usually lower than adult levels.

o In general drugs subject to biotransformation are eliminated more slowly in newborn than in adult.

oChronic exposure of the fetus to antiepileptic drugs throughout gestation may lead to induction of drug-metabolizing enzyme.

oSulfate conjugation seems to be as efficient in newborns as in adults, but conjugation with glucuronic acid is considerably reduced, reaching adult level only after 3 years of age.

oThis deficiency is responsible for the serious adverse effects observed in newborn after administration of chloramphenicol a drug that is ordinarily conjugated with glucuroni acid.

oThe clearance of morphine in newborn (1 to 4 days old) was less than half life found in older infants (6 vs. 24 ml/min/kg).

oThe amount of unchanged theophylline in urine in premature infants decreases with postnatal age, whereas the excretion of metabolites increases with age.

PLASMA PROTEIN BINDING IN NEWBORN:

oDifference in plasma protein binding and tissue binding of drugs have also been reported between newborn and adults.

o In each case binding in plasma protein is level in the newborns than in the adults.

o Increase in plasma protein binding is an increase in apparent volume of distribution in the newborn.

oThe relatively low plasma protein binding in neonates is often associated with elevated level of bilirubin, which is avidly bound to albumin and may complete with drug for binding sites.

o At one time it was thought that competition between drugs bilirubin for binding sites on albumin could result in displacement of bilirubin leading to its deposition in the central nervous system and kernicterus.

o decreased in plasma protein binding drugs and differences in body composition with respect to TBW and ECF.

RENAL EXCRETION IN NEWBORN:o Although the ratio of kidney weight to total

body weight in the newborns is twice that in the adults anatomically and functionally immature, all aspect of renal function are reduced.

o The difference process of renal excretion on mature at different rates,

o Average glomerular filtration rate is 38.5 ml/min.

o immature renal function affects the elimination of amino glycosides, indomethacine, digoxin, penicilline, sulfonamides and many other drugs.

oThe risk of ADR. In newborn is high.oThe elevated digoxin level in the

neonates are related to the low renal clearance of digoxin, which is half compared to children and adults with normal renal function.

DRUG METABOLISM IN CHILDREN:

o In general drug metabolism is impaired in neonates compared to adults.

oOlder infants age (6 months to 12 years) has higher drug metabolism capacity rates compared to adults.

for example, clindamycin theophylline valproic acidHas faster elimination rate.

o For dose determination body surface is found to be a better correlation factor compared to cardiac out put,

o Formula used to determine dosage form

Child dose= SA of child(m²) ------------------------------

o comparative study of procainamide in childrens and adults

Parameter Children Adults

Half life 1.7 hr 2.5 –5 hr

plasma clearance 20ml/min/kg 9 ml/min/kg

PREGNANCY

o Pregnancy is a condition associated with physiological changes that can affect the absorption, distribution and elimination of drugs.

o The increase in gastric ph, the decrease in gastric emptying rate and the slower motility associated with pregnancy can affect the rate and extent of drug absorption.

o The significant increase in plasma volume during pregnancy can increase the drug volume of distribution and the decrease in albumin serum concentration can decrease the protein binding of drugs.

oThe increase in cardiac output in general and the renal blood flow in particular during pregnancy increase the renal elimination rate of drugs such as ampicilline, digoxin, and lithium.