Pharmacokinetic variability exists both within and between individuals. The dose required to produce a therapeutic effect varies widely between patients due to factors like age, sex, weight, and drug interactions. Obesity affects the pharmacokinetic parameters of volume of distribution and clearance for some drugs. For highly lipophilic drugs, the volume of distribution is often increased in obese patients, while metabolism may be decreased. In neonates, drug metabolism pathways are generally less developed compared to adults, resulting in lower clearance and longer half-lives for many drugs. Gender can also influence pharmacokinetics due to differences in factors like muscle mass, vascular resistance and metabolic rates between males and females.

1. Pharmacokinetic variability

2. varibilityINTRERINDIVIDUAL VARIBILITY INTRAINDVIDUAL VARIBILITY

3. INTRERINDIVIDUAL VARIBILITYThe dose required to produce action varies from indvidual to indvidualThe doses reflect the various dosage strength in market

4. Varibility in dosesThe variability in dose of warfarin required to produce similar prothrombin action in 200 patients varies widely

5. Interindividual variabilityChange in plasma concentration of same subject when given in different occasionCauses-Age ,sex,diseases, weight, drug interaction etcHigh intrasubject variability difficult to prescribe the narrow therapeutic drugsIf high intrasubject variability in pharmacokinetic prescribed only if it has wide subject variability

6. histogramA.The plateau plasma con varies widely in260 patients receiving 25mg of nortryptiline orally three times dailyB.The con are log normally distrIbuted as seen in straight line

7. steps to Indvidlisation

8. Over view

9. Describing variabilityA,B are unimodel but C is bimodal signifying that they are are two major groups with in population With higher and lower clearance

10. Factors causing varibility

11. The development and subsequent marketing of drug

12. OBESITYPHARMACOKINTIC VARIBILITY

13. 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

14. Drug administrationDrug administration in obese patients is difficult because recommended doses are based on pharmacokinetic data obtained from individuals with normal weights;

15. Obesity affectspharmacokinetic parameters-volume of distribution (Vd), clearance (Cl) protein binding changed for some drugsi.v. anaesthetic drugsinhalational anaestheticsLipophilic drugs

16. Body mass indexbody 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

17. BMI

18. Dosage regimen

19. what ‘weightclinician must appreciate what ‘weight’ should be used to calculate dosage: totalbody weight (TBW), lean body mass (LBM) ideal body weight (IBW)?

20. TBW is actual body weightIBW is estimated by x =100 for adult males105 for adult females

21. lbmThe percentage of fat and lean body mass calculated based on - height(cm) -Weight(kg) -girth(inches) Percentage of fat = 90-2(height-girth)

22. Lean body massLBM can be calculated using the formulae

23. dosageMostly, dosage recommendations in the package inserts are scaled to TBWFor obsity-weight can then be multiplied by the published doses scaled to TBW = WEIGHT×DOSE ON LABEL

24. 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.

25. 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.

26. Lipophilic drugsHIGHILY LIPOPHILICDRUGSbarbiturates and benzodiazepines show significant increases in Vd for obese individuals. .Less lipophilic DRUGShave little or no change in Vd with obesityExceptions to this is remifentanil,

27. Volatile agentsHalothane is known to have considerable deposition in adipose tissuehepatic metabolism- halothane hepatitis

28. PropofolIn 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

30. Drug metabolismNeonates

31. neonatesInvitro studies indicate that variability much greater in first three months of life declines to adult activityNew born are higher for contreation toxicity due to development of delay drug metabolism

32. 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 adultsConjugation with glucornic acid reduced with increasing age

35. differences

36. Age groups

37. PROTEIN BINDING NEONATES

38. Protein bindingPlasma protein binding is less in newborn than adults Decrease Plasma protein binding is an increase in apparent volume of distribution in newbornLow plasma binding is due to elevation of bilrubin

39. competatiion relative low plasma binding associated with elevated levels of biliubrinBiluburin binds with albumin and many compete with drugs binding

40. GENDER

41. sexSex is an individual factor lead to interindividual differences in the metabolism of drugsdrugs that are metabolized by hepatic oxidation have lower metabolic clearance and longer elimination half-lives in women who are on oral contraceptives

42. sex differencesmuscle mass, disposition of muscle tissue, vascular resistance. gastric motility, secretion, metabolic rate

43. PHARMACOKINETIC CHANGESvolume of distribition and rate of metabolism changes Volume of distrubution for central compartment is more in malesPeripheral compartment of liophilic drug more in femalesEx- metablism of few drug in female oxazepam & metaprolol is slow in female

44. Pharmacokinetic Properties

45. referencesPharmacokinetics in obese patients by -Lu EC De Baerdemaeker MD slides of Approaching the In Silico Child Jeffrey S. Barrett, PhD, FCPBiopharmaceutics and clinical pharmacokineticsmilogibaldi ,PhD Clinical Pharmacokinetics Concepts and Applications