POPULATION PHARMACOKINETICS.docx

PHARMACOKINETIC CONSIDERATIONS IN OBESITY Calculate body mass index (BMI) and body surface area (BSA) when given the appropriate information. BMI – may not correspond to same fat/muscle composition between two people $\frac{Total\ Body\ weight\ (kg)}{\text{Heigh}t^{2}(meters)}$ Underweight: &lt...

PHARMACOKINETIC CONSIDERATIONS IN OBESITY Calculate body mass index (BMI) and body surface area (BSA) when given the appropriate information. BMI – may not correspond to same fat/muscle composition between two people $\frac{Total\ Body\ weight\ (kg)}{\text{Heigh}t^{2}(meters)}$ Underweight: < 18.5 kg/m2 Normal weight: 18.5 – 24.99 kg/m2 Overweight: > 25 kg/m2 Pre-obesity: 25 – 29.99 kg/m2 Obesity Class I: 30 – 34.99 kg/m2 Obesity Class II: 35 – 39.99 kg/m2 Obesity Class III (morbid obesity): > 40 kg/ m2 Use of BMI for drug dosing not adopted Clinically, a patient may be considered obese and morbidly obese when their TBW is 125%–190% and >195% of their IBW, respectively BSA – commonly used for dosing cancer patients Many clinicians use 2m2 for obese patients when BSA exceeds this arbitrary cut-off $$\sqrt{\frac{\text{height\ }\left( \text{cm} \right) \times \ weight\ (kg)}{3600}}$$ Explain the limitations of using BMI and BSA to dose medications All patients with same sex and height get same dose regardless of body composition AdjBW attempts to resolve this by adding IBW to some proportion of TBW Aminoglycosides: AdjBW calculations Indirect measures of body composition IBW, percent IBW Adjusted BW Relation to IBW Value above IBW Mildly obese 20-40% Moderately obese 40-100% Morbidly/severely obese Over 100% Know the equations for ideal body weight (IBW) and adjusted body weight (using a correction factor of 0.4) and be able to apply them accordingly Ideal body weight (IBW) Males: 50 kg + 2.3 kg (inches > 5 feet) Females: 45.5 + 2.3 kg (inches > 5 feet) Adjusted body weight (ABW) ABW = IBW + 0.4 (TBW –IBW) Potential problems using IBW for dosing All patients of the same sex and height get the same dose regardless of body composition Adjusted body weight (ABW) attempts to overcome this limitation by adding the difference between TBW and IBW to IBW for dosing purposes Adjusted body weight: commonly used for dosing aminoglycosides and other antibiotics Describe the impact of obesity on: hepatic drug clearance, renal clearance, and plasma protein binding Plasma protein binding changes in obesity Drugs primarily bound to albumin (i.e. phenytoin) show no change Drugs primarily bound to α1-acid glycoprotein (AAG) may show either an increase, decrease or no change Drug clearance in obesity CL is essential to consider for maintenance dosing regimen Clearance is controlled by physiology volume of blood from which drug is completely removed per unit of time, clearance may be affected by: Blood flow to an organ (i.e. the liver) ability of the organ to extract the drug from the blood Consider diseases more prevalent in obesity NAFLD, NASH Hepatic clearance Obesity linked to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic Accumulation of fat in the liver of obese individuals may alter hepatic blood flow Phase I Increased: CYP2D6 (↑), CYP2E1 (↑) Decreased: CYP3A (↓), CYP2C19 (↓) Unchanged/Unknown: CYP2C9, CYP1A2 Phase II: UGT In liver, increased for low hepatic extraction drugs In intestine, increased but minimal data Other Phase II: Glycine conjugation & acetylation appear to be unaffected Renal clearance Glomerular filtration Increased, decreased, or no change in GFR has been observed in multiple studies (using creatinine clearance as an index)* Increased clearance of aminoglycosides and vancomycin (up to 1.3 times IBW) have been observed Summary: “Clearance of a drug is largely determined by physiologic processes, some of which may be altered in the obese.” Tubular secretion: Increased* Tubular reabsorption: Inconclusive – limited data* * Not statistically significant Explain the impact of obesity on the volume of distribution of lipophilic and hydrophilic compounds Drug Distribution is Dependent on the volume, concentration, and rate: Tissue Size Permeability Perfusion (affinity of drugs for a tissue compartment) Physiological changes that affect drug distribution in obesity Changes in plasma protein binding constituents (↑) adipose tissue mass and lean body mass (↑) plasma volume (↑) cardiac output (↑) splanchnic blood flow Relevant Physiochemical Drug properties include: Lipid solubility Protein binding Molecular weight Degree of ionization Predicting changes in volume of distribution in obese individuals Hydrophilic (Polar) compounds Generally, same Vd because tend not to distribute to tissues Sometimes, increased due to adipose tissue composed of 30% water and increased LBM Aminoglycosides 0.26*(AdjBW); distribution to interstitial spaces will have larger volumes in obese patients Lipophillic (Non-polar) compounds Generally, larger Vd Exception: cyclosporine (little change with obesity) Calculate pharmacokinetic parameters such as volume, half-life, clearance, and elimination rate in obese individuals when given the necessary information Increase in volume is most important effect on PK profile Patients need higher dose and longer dosing interval Drug is “hanging around”, so longer half-life Describe the impact of obesity on phenytoin and lithium pharmacokinetics Phenytoin Half-life is longer in obese patients At first, concentrations will be lower than that of normal patient After a given period of time, concentrations will be higher in obese patients than those of normal weight patients Vd significantly greater in obese persons Clearance is greater but not significant (therefore Vd is more important here) Lithium Similar to sodium; volume of distribution is lower since it doesn’t get into fat tissue well Clearance is greater lower half-life Less tubular reabsorption Vd significantly less valuable Half-life was almost significant (since it depends on Vd and Cl) Li is excreted mainly by GFR + tubular reabsorption; as GFR cannot change, then ↑ Li Cl is likely due to ↓ tubular reabsorption. Obese patients may require higher doses of lithium