Drug Disposition in Obesity & Protein-Calorie Malnutrition

Drug Disposition in Obesity & Protein-Calorie Malnutrition JBoullata, PharmD, RPh, BCNSP Associate Professor of Pharmacology & Therapeutics -and- Pharmacy Specialist in Nutrition Support University of Pennsylvania, Philadelphia, PA, USA

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations

Clinical Variability Drug response can differ between patients Appropriate care requires an appreciation of factors that influence drug disposition and effect Disposition absorption, distribution, and elimination Effect physiologic action at tissue/cell target Sources of variability Age, life stage, sex, genotype, disease states, and nutrition status

Classification of Drug-Nutrient Interactions Pharmacotherapy 2005;25:1789

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations Pharmacokinetics Drug distribution Drug elimination PCM Obesity

Dose of drug administered Drug concentration in systemic circulation ABSORPTION Drug in tissues of distribution Drug metabolized or excreted Pharmacokinetics Drug concentration at site of action Pharmacologic Effect Clinical Response Pharmacodynamics TOXICITY EFFICACY

Drug Distribution Movement of the active drug from the blood to the site(s) of effect; involves crossing cell membranes Determining factors are related to: Body Body composition, blood flow, tissue size and permeability Drug Drug lipophilicity, plasma-protein binding, degree of ionization, tissue binding

Drug Distribution Volume of distribution (V d ) for a drug is the theoretical body volume that the drug would have to distribute into if the drug concentration everywhere were to be the same as that found in plasma following administration

Drug Elimination Metabolism Transformation of a drug s structure by enzymatic reaction Liver and gut are predominant sites Phase I and II metabolic reactions

Metabolizing Enzymes Phase I Phase II

Metabolism Drug Elimination Transformation of a drug s structure by enzymatic reaction Liver and gut are predominant sites Phase I and II metabolic reactions Excretion The removal of a drug and it s metabolite(s) from the body Renal and hepatic routes are the most common Clearance (Cl) is the volume of a compartment, per unit of time, that is cleared of a drug due to elimination

Protein-Calorie Malnutrition Nutrient / metabolic needs not being met Chronic deficits of protein and energy Micronutrient deficits as well

Protein-Calorie Malnutrition (Pediatrics) Term Underweight Short Stature Wasting Stunting Definition Weight-for-Length <5 th percentile Length/Height-for-Age <5 th percentile Weight-for-Height 2 + SD < mean Height-for-Age 2 + SD < reference

Protein-Calorie Malnutrition (Adults) Term Definitions BMI (kg/m 2 ) % Ideal Wt Underweight < 18.5 < 70-80

Obesity Nutrient / metabolic needs not being met Chronic caloric imbalance Complex disorder involving environmental and genetic factors

Obesity (Pediatrics) Term Overweight Obese Severely Obese Definition BMI-for-Age 85-95 th percentile BMI-for-Age 95 th percentile BMI-for-Age 99 th percentile

Obesity (Adults) Term Definitions BMI (kg/m 2 ) % Ideal Wt Overweight 25-30 120 Obese 30 130 Extremely Obese 40 180

80 kg FM FFM Normal 6 0 (BMI = 24)

Dosing Weight Depends on The substance being dosed How it is handled differently in Obesity or PCM Body size metric should account for Age and ethnicity As well as height, weight, sex Remain robust at the extremes

Dosing Weight Lean body Weight (LBW) Approximates the fat-free mass Total Body Weight (TBW) Used most often, unless: BMI >30, or volume overloaded Adjusted Body Weight (Adj-BW) Adjusting the TBW with a correction factor (cf) will depend on the substance being dosed Adj-BW = LBW + (cf)(tbw LBW)

Adipose Tissue Compartment Subcutaneous AT Superficial Deep Internal AT Visceral Intra-thoracic Intra-abdominal Intra-pelvic Non-visceral

Obes Res 2003;11:5

6 2 = 188 cm 174lbs = 79 kg BMI = 22 kg/m 2

Pharm World Sci 2009;31:422

Body Weight Equations Body Weight Term Equation for Men Equation for Women Ideal Weight 52 kg + 1.9 kg/in > 5 ft 49 kg + 1.7 kg/in > 5 ft Optimum Weight 106 lbs + 6 lbs/in > 5 ft 100 lbs + 5 lbs/in > 5 ft 48.2 kg + 2.7 kg/in > 5 ft 45.5 + 2.3 kg/in > 5 ft Lean Weight 50 kg + 2.3 kg/in > 5 ft 45.5 kg + 2.3 kg/in > 5 ft Predicted Normal Weight (1.57)(kg) (0.0183)(BMI)(kg) (1.75)(kg) (0.0242)(BMI)(kg)

Body Weight Equations Body Weight Term Equation for Men Equation for Women Body Cell Mass Lean Mass (kg)[79.5 (0.24)(kg) (0.15)(y)] (kg)[69.8 (0.26)(kg) (0.12)(y)] 73.2 73.2 (1.1013)(kg) (0.01281)(BMI)(kg) (1.07)(kg) (0.0148)(BMI)(kg) Lean Body (9270)(kg) (9270)(kg) Weight 6680 + 216(BMI) 8780 + 244(BMI)

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations

Altered Physiology Malnutrition (protein-calorie or obesity) induce changes in body composition and function These changes can influence drug disposition

Altered Physiology Composition Function AT H 2 O Lean RMR CO GFR Prtn Synth PCM OB??

50 kg FM FFM FM FFM 80 kg PCM Normal (BMI = 15) 6 0 (BMI = 24)

120 kg 80 kg FM FM FFM FFM Normal Obese 6 0 (BMI = 24) (BMI = 36)

40 year-old 5 6 = 1.68 m 250 lbs = 114 kg BMI = 40 kg/m 2

Kidney Int 2006;70:1832

BMI Tertile Parameter I (19.4-24.8 kg/m 2 ) II (25.1-28.4 kg/m 2 ) III (28.9-41.1 kg/m 2 ) P-value Body Weight 64 72 95 <0.05 Visceral Organs 16 18 20 <0.05 Muscle Mass 20 22 29 <0.05 Adipose Tissue 16 20 32 <0.05 Bone Mass 11 13 13 ns Total Body Water 37 39 45 <0.05 Kidney Int 2006;70:1832

BMI Category Parameter I (19.1-29.9 kg/m 2 ) II (30-39.9 kg/m 2 ) III (40-48.2 kg/m 2 ) Total Body Water (L) 38 41 42 Total Body Water (%) 62 44 40 Extracellular Fluid (L) 15 19 19 Extracellular Fluid (%) 39 45 46 Eur J Clin Nutr 2005;59:155

Kidney Int 2006;70:1832

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations

Altered Pharmacokinetics Absorption Distribution Metabolism Excretion PCM ø, Free drug Slow ø Renal Cl, ø severe ø, mild ø CYP3A CYP1A2, 2E1 OB ø,, ø Free drug (αagp), ø CYP3A Renal Cl ø, Free drug (ALB) ø CYP1A2 CYP2E1 UGT

PCM: Distribution Physiologic Changes Body composition, transport proteins, hormone regulation Influence on Kinetics Drug V d may be increased or decreased Unbound drug fraction may be increased

Physiologic Changes PCM: Elimination Reduced CO, fatty liver, mitochondrial damage, reduced microsomes, altered metabolism, reduced GFR Influence on Kinetics Hepatic Clearance Severe PCM decreases oxidation, and possibly conjugation Mild PCM may increase, or not influence oxidative clearance Renal Clearance Severe PCM may decrease, or not influence renal drug clearance

Body Comp Metric Used Drugs Investigated for Influence of Obesity LBW Caffeine Enoxaparin Fentanyl Inulin IBW Acetaminophen Dalteparin Lidocaine Quinine Alprazolam Desmethyldiazepam Lithium Ranitidine Amikacin Dexfenfluramine Lorazepam Remifentanil Antipyrine Diazepam Methylprednisolone Sotalol Aspirin Digoxin Midazolam Sufentanil Bisoprolol Doxorubicin Nebivolol Theophylline Busulfan Gentamicin Nitrazepam Tobramycin Caffeine Glipizide Oxazepam Trazadone Cefotaxime Glyburide Phenytoin Triazolam Cefotiam Ibuprofen Prednisolone Vancomycin Cimetidine Ifosfamide Procainamide Vercuronium Ciprofloxacin Labetolol Propranolol Verapamil Cyclosporin BMI Antipyrine Carbamazepine Enoxaparin Thiopental Caffeine Chlorzoxazone Rocuronium Triazolam Compiled by Han et al Clin Pharmacol Ther 2007;82:505

Obesity: Distribution Physiologic Changes Altered body composition, and carrier proteins Influence on Kinetics Lipophilic drugs May or may not have larger V d (L/kg) Hydrophilic drugs May or may not have a larger V d (L/kg)

Altered Vd in Obesity Drug Non-Obese Obese Diazepam 1.53 L/kg 2.81 L/kg Cyclosporine 4.5 L/kg 2.5 L/kg Digoxin 14.3 L/kg 10.7 L/kg Ampicillin 0.4 L/kg 0.6 L/kg Cefotaxime 0.25 L/kg 0.4 L/kg Ranitidine 1.4 L/kg 0.8 L/kg

Obesity: Elimination Physiologic Changes Increased CO, fatty liver, portal inflammation and fibrosis, increased renal plasma clearance and CrCl Influence on Kinetics Hepatic Clearance Phase I: increased, decreased or unchanged Phase II: increased or unchanged Renal Clearance Renal drug clearance may be increased

Altered Cl in Obesity Drug Non-Obese Obese Prednisolone 8.2 L/h 11.1 L/h Lorazepam 3.8 L/h 6.1 L/h Procainamide 19 L/h 22 L/h

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations

Antibiotics in PCM Drug V d Cl Aminoglycosides Chloramphenicol - Penicillin - Quinine Isoniazid -

Antibiotics in Obesity Drug V d Cl Comment Aminoglycosides ø, cf = 0.4 Antifungals???Total body weight β-lactams, ø, cf = 0.3 Fluoroquinolones cf = 0.45 Linezolid? cf = 0.27 Vancomycin ø Total body weight

Drug Dosing in Obesity Am J Health-Syst Pharm 2005;62:464 A 43 yo man hospitalized with bacterial cellulitis weighing 286 kg (BMI 86) is treated with: Cefazolin IV x 14 d then Linezolid 600 mg bid x 21 d and has a measured CrCl 75 ml/min. Pharmacokinetic parameters (linezolid) Patient Normal VD 135.7 L (0.47 L/kg) 40-50 L (0.61-0.67 L/kg)

Drug Dosing in Obesity Ann Pharmacother 2005;39:262 Hospitalized patients with sepsis may receive drotrecogin-α (APC) at 24 μg/kg/h x 96 h usually based on total body weight but controversial for obese patients Parameter 135 kg > 135 kg P-value Patients (#) 32 20 Weight (kg) 93 158 <0.001 BMI (kg/m²) 33 55 <0.001 Drug Cl (L/h/kg) 0.45 0.42 0.692

Drug Dosing in Obesity Am J Health-Syst Pharm 2009;66:1288 A 60 yo man admitted with a presumptive diagnosis of Herpes encephalitis; standing 5 7 (1.7 m) and weighing 108.9 kg (BMI 38) with BUN:Cr 9 mg/dl:0.7 mg/dl: Acyclovir 1000 mg IV every 8 h Moxifloxacin 400 mg IV daily Doxycycline 100 mg IV every 12 h Develops acyclovir-induced nephrotoxicity by hospital day #3 (peak BUN:Cr 57 mg/dl:5.5 mg/dl)

Drug Dosing in Obesity Am J Health-Syst Pharm 2009;66:1288 A 60 yo man admitted with a presumptive diagnosis of Herpes encephalitis; standing 5 7 (1.7 m) and weighing 108.9 kg (BMI 38) with BUN:Cr 9 mg/dl:0.7 mg/dl: Acyclovir 1000 mg IV Based every on 8 htbw 9.2 mg/kg Moxifloxacin 400 mg IV daily But given Vd/kg, dose by LBW Doxycycline 100 mg IV LBW every of ~60 12 hkg 17 mg/kg Develops acyclovir-induced nephrotoxicity by hospital day #3 (peak BUN:Cr 57 mg/dl:5.5 mg/dl)

Drug Dosing in Obesity Am J Health-Syst Pharm 2009;66:1288 A 60 yo man admitted with a presumptive diagnosis of Herpes encephalitis; standing 5 7 (1.7 m) and weighing 108.9 kg (BMI 38) with BUN:Cr 9 mg/dl:0.7 mg/dl: Acyclovir 1000 mg IV Based every 8 on htbw 9.2 mg/kg Moxifloxacin 400 mg IV daily Doxycycline 100 mg IV LBW every of ~60 12 hkg 17 mg/kg Develops acyclovir-induced nephrotoxicity by hospital day #3 (peak BUN:Cr 57 mg/dl:5.5 mg/dl) But given Vd/kg, dose by LBW

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations

PCM Patients Given the limited data on the impact of PCM on most drugs, use caution in managing these patients especially when using narrow therapeutic index drugs Use available drug-specific data and patientspecific data to develop appropriate dosing and monitoring regimens

Obese Patients Use available drug-specific data and close patient monitoring to design dosing strategies in obesity General approach For loading dose evaluate the influence on V d For maintenance dosing evaluate the influence on Cl

An Empiric Guide To Weight-Based Dosing in Obesity Loading Dose VD/kg of TBWOB : VD/kg of TBWNOB If > 1 use TBW If 0.7-1 use an Adj-BW If < 0.7 use LBW Maintenance Dose ClT OB : ClT NOB If > 1 use TBW If < 1 use an Adj-BW or LBW

Obese Patients Loading Dose (base on V d ) Markedly decreased V d /kg use LBW Slightly decreased V d /kg use an Adj-BW No real change or increased in V d /kg use TBW Maintenance Dose (base on Cl) If Cl decreases or does not change use LBW If Cl increases with weight use TBW In the absence of data err on the side of dosing based on LBW

Medication Dosing Weight in Obesity Example Loading Dose Maintenance Dose Aminoglycosides Adj-BW ª Adj-BW ª, or by therapeutic response Amphotericin TBW TBW Atracurium LBW TBW Carbamazepine TBW, Adj BW LBW Ciprofloxacin Adj-BW ª Adj-BW ª Cyclosporine LBW LBW Flucytosine LBW LBW Linezolid Adj-BW ª Adj-BW ª, or by therapeutic response Lithium LBW Larger than non-obese Phenytoin Adj-BW ª Adj-BW ª Propofol TBW TBW Theophylline LBW Adj-BW ª Vancomycin TBW TBW Vecuronium LBW LBW Verapamil TBW LBW Adj-BW = adjusted body weight; LBW = lean body weight; TBW = total body weight ª = correction factor varies with the drug and study findings

Outline Introduction Definitions Physiological Changes Pharmacokinetic Changes Antimicrobial Examples Recommendations