obsity

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