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Pharmacokinetic variability
VARIBILITY
INTRERINDIVIDUAL VARIBILITY
INTRAINDVIDUAL VARIBILITY
INTRERINDIVIDUAL VARIBILITY
The dose required to produce action varies from indvidual to indvidual
The doses reflect the various dosage strength in market
VARIBILITY IN DOSES
The variability in dose of warfarin required to produce similar prothrombin action in 200 patients varies widely
INTERINDIVIDUAL VARIABILITY
Change in plasma concentration of same subject when given in different occasion
Causes- Age ,sex,diseases, weight, drug interaction etc
High intrasubject variability difficult to prescribe the narrow therapeutic drugs
If high intrasubject variability in pharmacokinetic prescribed only if it has wide subject variability
HISTOGRAM
A.The plateau plasma con varies widely in260 patients receiving 25mg of nortryptiline orally three times daily
B.The con are log normally distrIbuted as seen in straight line
STEPS TO INDVIDLISATION
Estimation of pk para
meters
Evaluate
extent of
variability
Attributin
g variability
Design of new dosag
e regim
en
OVER VIEW
DESCRIBING VARIABILITY
A,B are unimodel but C is bimodal signifying that they are are two major groups with in population With higher and lower clearance
FACTORS CAUSING VARIBILITY
The development and subsequent marketing of drug
PHARMACOKINTIC VARIBILITY
OBESITY
OBESITY
a condition that is characterized by excessive accumulation and storage of fat in the body and that in an adult is typically indicated by a body mass index of 30 or greater
DRUG ADMINISTRATION
Drug administration in obese patients is difficult because recommended doses are based on pharmacokinetic data obtained from individuals with normal weights;
OBESITY AFFECTS pharmacokinetic parameters-
volume of distribution (Vd), clearance (Cl) protein binding
changed for some drugs i.v. anaesthetic drugs inhalational anaesthetics Lipophilic drugs
BODY MASS INDEX
body mass index n a measure of body fat that is the ratio of the weight of the body in kilograms to the square of its height in meters
BMI Women Men
underweight <19.1 <20.7
ideal weight 19.1-25.8 20.7-26.4
marginally overweight 25.8-27.3 26.4-27.8
overweight 27.3-32.3 27.8-31.1
very overweight or obese >32.3 >31.1
Dosage regimen
WHAT ‘WEIGHT
clinician must appreciate what ‘weight’ should be used to calculate dosage: totalbody weight (TBW), lean body mass (LBM) ideal body weight (IBW)?
TBW is actual body weight
IBW is estimated by
x =100 for adult males
105 for adult females
LBM
The percentage of fat and lean body mass
calculated based on - height(cm) -Weight(kg) -girth(inches)
Percentage of fat = 90-2(height-girth)
LEAN BODY MASS
LBM can be calculated using the formulae
DOSAGE
Mostly, dosage recommendations in the package inserts are scaled to TBW
For obsity- weight can then be multiplied by the
published doses scaled to TBW = WEIGHT×DOSE ON LABEL
NOMOGRAM(MALE)
Nomogram for male patients relating total body weight (kg), height(cm), and gender with lean body mass (LBM) using the formulaLBM = 1.1(weight) 128(weight/height)2.
NOMOGRAM (FEMALES)
Nomogram for female patients relating total body weight (kg),height (cm), and gender with lean body mass (LBM) using the formulaLBM = 1.07(weight) – 148(weight/height)2.
LIPOPHILIC DRUGS
HIGHILY LIPOPHILICDRUGS
barbiturates and benzodiazepines show significant increases in Vd for obese individuals.
.
Less lipophilic DRUGS
have little or no change in Vd with obesity
Exceptions to this is remifentanil,
VOLATILE AGENTS
Halothane is known to have considerable deposition in adipose tissue
hepatic metabolism- halothane hepatitis
PROPOFOL In morbidly obese patients, the
induction dose of propofol can be calculated on IBW.
Although propofol is highly lipophilic,does not accumulate in obese patients.
So the dosage of propofol for maintenance of anaesthesia in obese and lean same
DRUG METABOLISM
Neonates
NEONATES
Invitro studies indicate that variability much greater in first three months of life declines to adult activity
New born are higher for contreation toxicity due to development of delay drug metabolism
Enzymatic system required for drug metabolism are higher in neonates and lower in adults
Chornic exposure of foetus to epliptic drugs leads to induction of drug metabolism enzymes
Sulfate conjugation seems to be efficient in newborn as in adults
Conjugation with glucornic acid reduced with increasing age
Enzyme Development Common Pediatric Drugs Using the Pathway
Cyp1A2 appears at 1–3 months; adult activity 6 months–2 years; exceeds adult activity in early childhood
Acetaminophen, caffeine, diazepam, theophylline, phenytoin, R-warfarin
Cyp2D6 appears within hours of birth; 20% activity 1 month postnatal; adult activity reached by 1–3 years
Chlorpromazine, codeine, dextromethorphan, fluoxetine, hydrocodone, methadone, morphine, paroxetine, propranolol
Cyp2C9 appears during 1st week of life; 50% activity by 1 month; adult activity reached by 6 months of age
Amitriptyline, diazepam, ibuprofen, omeprazole, phenytoin, topiramate, S-warfarin
Cyp3A4 Cyp3A7 is fetal form of enzyme with high activity in uteroActivity appears during 1st week of life
Carbamazepine, cyclosporine, dexamethasone, diltiazem, erythromycin, fluconazole
Enzyme Development Common Pediatric Drugs Using the Pathway
Alchohol dehydrogenase
3%–4% of adult activity in infants; adult activity levels by 4–5 years
Benzyl alcohol, ethanol, steroids
Glucuronide conjugation
Low levels of activity in utero; 25% of adult activity by 3 months of age; adult activity by 3–30 months of age
Morphine, phenobarbital, acetaminophen, propofol,,
Acetylation Low levels of activity in utero; adult activity by 1–3 years
Sulfonamides, hydralazine, procainamide
Sulfate conjugation
High levels of activity in utero exceeds adult activity in infancy
Acetaminophen, steroids
Methylation 30% adult activity in utero; exceeds adult levels of activity in newborns; insignificant activity in adults
Theophylline, acetaminophen
DIFFERENCES
PPhhyyssiioollooggiiccaall FFuunncctt iioonn NNeeoonnaattee II nnff aannttss CChhiillddrreenn
GGaassttrr iicc ppHH >>55 44 ttoo 22 NNoorrmmaall ((22--33)) BBiilliiaarryy FFuunncctt iioonn II mmmmaattuurree NNeeaarr aadduulltt AAdduulltt ppaatttteerrnn GGaassttrr iicc EEmmppttyyiinngg TTiimmee II rr rreegguullaarr II nnccrreeaasseedd SSlliigghhtt .. iinnccrreeaasseedd II nntteesstt iinnaall MMoott iilliittyy RReedduucceedd II nnccrreeaasseedd SSlliigghhtt .. iinnccrreeaasseedd II nntteesstt iinnaall SSuurrff aaccee AArreeaa RReedduucceedd ((??)) NNeeaarr aadduulltt AAdduulltt ppaatttteerrnn SSppllaanncchhnniicc BBlloooodd FFllooww RReedduucceedd NNeeaarr aadduulltt AAdduulltt ppaatttteerrnn MMiiccrroobbiiaall CCoolloonniizzaatt iioonn 11oo aaeerroobbeess NNeeaarr aadduulltt 11oo aannaaeerroobbeess II nntteesstt iinnaall MMeettaabboolliissmm ((??)) ((??)) ((??)) II nntteesstt .. DDrruugg TTrraannssppoorrtt ((??)) ((??)) ((??))
AGE GROUPS
AGE GROUPS AGE
Premature Neonates ≤ 1 wk
Full Term Neonates ≤ 1 wk
Newborns 1 wk- 2 months
Early infants 2-6 months
Crawlers & Toddlers 6 months -2 yrs
Pre-Adolescents 2-12 years)
Adolescents 12-18 years
Adults >18 YEARS
PROTEIN BINDING
NEONATES
PROTEIN BINDING
Plasma protein binding is less in newborn than adults
Decrease Plasma protein binding is an increase in apparent volume of distribution in newborn
Low plasma binding is due to elevation of bilrubin
COMPETATIION
relative low plasma binding associated with elevated levels of biliubrin
Biluburin binds with albumin and many compete with drugs binding
GENDER
SEX Sex is an individual factor lead to interindividual differences in
the metabolism of drugs drugs that are metabolized by hepatic
oxidation have lower metabolic clearance and longer elimination half-lives in women who are on oral contraceptives
SEX DIFFERENCES
muscle mass, disposition of muscle tissue, vascular resistance. gastric motility, secretion, metabolic rate
PHARMACOKINETIC CHANGES
volume of distribition and rate of metabolism changes
Volume of distrubution for central compartment is more in males
Peripheral compartment of liophilic drug more in females Ex- metablism of few drug in female
oxazepam
& metaprolol is slow in female
PHARMACOKINETIC PROPERTIES Parameter
Observation
Absorption Generally, absorption is lower in women
Volume of distribution
Volume of distribution of lipophilic drugs is higher and volume of distribution of hydrophilic drugs is lower in women
Protein binding No clinically significant difference
Elimination half-life Longer in women than in men
REFERENCES
Pharmacokinetics in obese patients by -Lu EC De Baerdemaeker MD
slides of Approaching the In Silico Child Jeffrey S. Barrett, PhD, FCP Biopharmaceutics and clinical pharmacokinetics milo gibaldi ,PhD Clinical Pharmacokinetics Concepts and
Applications