Impact of Obesity on Medication Dosing John C. Williamson, PharmD, BCPS, AAHIVE Wake Forest University Baptist Medical Center Winston-Salem, NC Objectives Determine what constitutes the various forms of obesity as it relates to medical care Discuss the clinical implications of obesity Review the pharmacokinetic and pharmacodynamic changes that occur with obesity Provide recommendations for drug dosing in the obese patient Audience Poll: Question 1 Obesity American society obesogenic Overweight and obesity determined by body mass index (BMI) BMI = Weight (kg)/[height (m)] 2 Overweight: 25 29.9 Obese: 30 (28% of adult Americans) Morbidly obese: 40 (5% of adult Americans) Age-adjusted percentage of adults aged 20 years who are obese, 2007 Counties in the top and bottom two quintiles of both diabetes and obesity, 2007 MMWR 58:1259-1263, 2009 CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics MMWR 58:1259-1263, 2009 CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics 1
Age-adjusted Percentage of U.S. Adults Who Were Obese or Who Had Diagnosed Diabetes Obesity (BMI 30 kg/m 2 ) 1994 2000 Diabetes 2008 No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0% 1994 2000 2008 No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0% CDC s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics Clinical implication of obesity Coronary artery disease Type 2 diabetes Cancer (endometrial, ovarian, colon) Hypertension Dyslipidemia Stroke Non-alcoholic fatty liver disease Sleep apnea Osteoarthritis SC healthcare expenditures attributable to obesity Total population: 6.2% Medicare population: 7.7% Medicaid population: 10.6% Obesity Research 2004;12(1):18 24. PK effects of obesity Potential for alteration Distribution, Vd Clearance Absorption is not altered Protein binding is not altered One-Compartment Model Drugs that rapidly equilibrate with peripheral compartments Plasma concentrations decrease log-linear linear Drugs that equilibrate slowly with peripheral tissues Biphasic line Rapidly Perfused Peripheral Compartment represents drug movement into less well- perfused spaces Peripheral Compartment 2
Rapidly Perfused Rapidly Perfused Peripheral Compartment represents drug movement into less well- perfused spaces Peripheral Compartment Peripheral Compartment represents drug movement into less well- perfused spaces Peripheral Compartment Vd in obese patients Larger peripheral compartment Larger Peripheral Compartment Mostly adipose tissue 80 Lean tissue accounts for 70 20-40% of extra 60 Blood volume also 50 increased 40 Blood flow per gram of 30 fat depends of degree of 20 obesity 10 0 Percent of cardiac output Fat Lean Visceral Clin Pharmacokinet 2000;39:215-31. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications, 1995. Factors that affect tissue penetration Drug factors Molecular size Ionization Ability to cross biological membranes Lipid solubility Protein binding Patient factors Blood flow Ventricular function Hepatic function n What about clearance in obesity? Liver Non-alcoholic fatty liver disease altered hepatic blood flow CYP450 2E1 activity increased Phase II metabolism increased (lorazepam and acetaminophen) Kidneys Slightly increased GFR in morbid obesity Creatinine clearance estimates less accurate GFR not proportional to TBW Clin Pharmacokinetics 2010;49:71-87. Clin Pharmacokinetics 2010;49:71-87. 3
Creatinine Clearance Creatinine Clearance Cockcroft and Gault = (140 Age) (IBW kg) (72) (SCr) Multiply by 0.85 if female Measured GFR in morbid obesity Morbidly Obese (n=7) Normal Weight (n=7) BMI (kg/m 2 ) 46.2 +/- 5.5 21.8 +/- 1.9 TBW (kg) 114.3 +/- 15.8 58.8 +/- 6.2 IBW (kg) 52.8 +/- 6.2 55.8 +/- 6.1 GFR (ml/min) measured by 116.0 +/- 45.2 93.5 +/- 28.8 [ 125 I]Na iothalamate GFR (ml/min/1.73m 2 ) estimated by 4-variable MDRD 100.8 +/- 28.7 93.0 +/- 13.4 CrCl estimated by Cockcroft- Gault using: TBW 226.9 +/- 69.1 112.2 +/- 19.7 IBW 101.0 +/- 21.1 107.6 +/- 24.2 Cockcroft DW, Gault MH. Nephron 1976;16:31-41. Antimicrob Agents Chemother 2007;51:2741-7. Audience Poll: Question 2 Dosing considerations in obesity Clinical scenario Severity of illness Other patient variables, e.g. age Narrow therapeutic window Too low ineffective treatment Too high toxicity Titratable? Availability of therapeutic drug monitoring Important drugs Anticoagulants Antibiotics Chemotherapy Neuromuscular blockers Anesthesia Oral contraceptives Unfractionated heparin (UFH) Prospective, observational cohort 1250-bed tertiary teaching hospital Hospital policy recommends using TBW Nurse-driven nomogram for adjustments Morbidly obese patients matched to obese group and under/normal weight group N = 273 (94, 92, and 87) Ann Pharmacother 2010;44:1141-51. 4
UFH infusion rates (units/kg/h) Outcome Measure Weight Class (BMI) P value 40 25-39.9 <25 Infusion rate at 1 st therapeutic aptt VTE 12.5 13.2 15.6 0.005 Non-VTE-related indication 10.8 12.3 12.6 0.004 All patients 11.5 12.5 13.5 0.001 Infusion rate at 2 consecutive therapeutic aptts VTE 11.9 13.2 15 0.034 Non-VTE-related indication 11.2 12.6 12.3 0.073 All patients 11.5 12.7 13 0.016 UFH dosing in obesity Vd mimics blood volume Dosing on TBW may over-shoot Using an adjusted weight is reasonable IBW + 0.3(TBW-IBW) IBW + 0.4(TBW-IBW) Need data on clinical outcomes Ann Pharmacother 2010;44:1141-51. Enoxaparin dosing in obesity Retrospective cohort study CRUSADE initiative: national quality improvement registry of patients with non-st elevation ACS 403 medical centers in U.S. Extracted data on patients treated with enoxaparin 2004-20062006 Examined enoxaparin dose and bleeding risk Enoxaparin dosing n (total) = 19,061; n (101-120kg) = 2,730; n (121-150kg) = 994; n (>150kg) = 175 Pharmacother 2009;29:631-8. Pharmacother 2009;29:631-8. Risk of bleeding with enoxaparin Total Body Weight (kg) 100 (n=8762) 101-120 (n=1388) 121-150 (n=409) >150 (n=35) Body Mass Index <18.5 (n=348) 18.5-24.9 (n=4411) 25.0-29.9 (n=6874) 30 (n=7428) Unadjusted Rate of Bleeding (%) Overall 7.8 5.9 6.0 8.0 10.6 8.5 7.1 6.9 Reduced Dose Enoxaparin 9.6 7.3 6.1 6.5 Recommended Dose Enoxaparin 6.6 4.6 5.6 11.4 Adjusted Odds Ratio (95% CI) 0.78 (0.69-0.89) 0.68 (0.48-0.95) 0.99 (0.57-1.70) 2.42 (0.70-8.37) 0.94 (0.71-1.26) 1.00 (0.85-1.18) 0.93 (0.80-1.08) 0.97 (0.84-1.11) Take home points about dosing enoxaparin for ACS Clinicians often reduce the dose in obese patients, especially if 120kg U-shaped curve for bleeding risk vs. weight Dose reduction not necessary if <150kg Caution advised if using 1mg/kg and weight >150kg (cap doses at 150mg?) Efficacy trade off? Need clinical outcomes data Pharmacother 2009;29:631-8. 5
The waters get muddy What about antibiotics? 12 obese & 12 lean subjects Ciprofloxacin 2.85mg/kg TBW IV x 1 Plasma and tissue concentrations measured Obese Plasma Skeletal muscle Adipose tissue Normal weight Plasma Skeletal muscle SC adipose tissue Cmax 6-hr conc AUC 9.97* 2.16 3.10 2.59 1.72 2.12 0.44 0.11 0.09 0.19 0.06 0.05 6.18* 2.57 2.68 3.02 2.28 2.21 Int J Obesity 2001;25:354-8. Impaired ciprofloxacin penetration Vancomycin 28-year-old morbidly obese man presents with breast abscess and cellulitis, WBC 18.9 Weight = 540kg Underwent irrigation and debridement Vancomycin is started overnight at 1,500mg Q12h Consider total body weight when dosing ciprofloxacin Possible increased risk of toxicity in obese patients Int J Obesity 2001;25:354-8. Vancomycin course Vancomycin dose Level (mcg/ml) Day 1: 1500mg Q12h 3 hours before 3 rd dose = 7 Day 2: 1500mg Q8h 1 hour before 3 rd dose = 8 Just before 5 th dose = 6 Day 5: 2000mg Q8h 2 hours before 6 th dose = 17 Vancomycin Obesity may delay time to therapeutic steady- state trough Use TBW to determine doses Consider loading dose Proportionality between dose and TBW may be lost among super obese (BMI 50) 6
Cefuroxime prophylaxis Cefuroxime 1.5gm IV surgical prophylaxis Abdominal surgery n=6 Weights 109-140kg140kg Plasma, skeletal muscle, adipose concentrations measured Antibiotic dosing in obesity Ideal/lean weight High end of normal dosing range Adjusted weight Total weight Acyclovir Beta-lactams Aminoglycosides Vancomycin Amphotericin B lipid complex Fluoroquinolones Daptomycin Trimethoprim- sulfamethoxazole Linezolid Quinupristindalfopristin Macrolides Amphotericin B deoxycholate Clindamycin Fluconazole Metronidazole Doxy-Minocycline Int J Antimicrob Agents 2009;34:231-5. Conclusions PK/PD alterations exist, but not extreme No one single drug factor is predictive Drug-specific Focus on drugs with narrow therapeutic index Risk versus benefit Stay up to date Area of much needed research FDA has not adapted Review of 84 NDAs for injectable medications (2004-2009) Assigned usefulness score Weight descriptor in package insert Pivotal studies included patients with extremes of weight Additional PK studies in patients with extremes of weight 0 of 84 medications had usefulness score of 2 or higher Am J Health-Syst Pharm 2010;67:1948-50. 7