Advertisement

Special Populations: Profiling the Effect of Obesity on Drug Disposition and Pharmacodynamics

  • Kenneth T. MooreEmail author
Living reference work entry

Abstract

The health implications of obesity remain a global issue with approximately 13% of the world’s population categorized as obese (body mass index [BMI] ≥30 kg/m2) in 2016 (World Health Organization, Obesity and overweight. http://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 8 Oct 2018, 2018). Obesity is typically a consequence of either excess food intake, lack of physical activity, genetic predisposition, or a combination thereof. Its impact is multifaceted, not only on the patient’s health leading to a myriad of disease states directly related to obesity, but also on the management of these diseases and other common medical conditions that frequently occur. Obesity-related changes in normal physiology, such as alterations in lipid content, plasma proteins, drug metabolizing enzymes, drug transporters, and blood flow, can affect the disposition (absorption, distribution, metabolism, and excretion) and pharmacodynamics of commonly prescribed drugs, thereby altering their pharmacologic profiles. Hence, an understanding of these pharmacologic changes is necessary to ensure proper treatment is exercised. Unfortunately, our understanding of obesity-related changes in drug pharmacology in addition to the overall safety and efficacy is limited, as clinical trials rarely focus specifically on this population. Therefore, the purpose of this chapter is to provide a review of the available literature assessing the effects of obesity on the disposition and pharmacodynamics of some of the most commonly prescribed drugs. This chapter is a review only; careful clinical decision making should always be used when applying literature from the population to individual patients and scenarios.

References and Further Reading

  1. Abernethy DR, Schwartz JB (1988) Verapamil pharmacodynamics and disposition in obese hypertensive patients. J Cardiovasc Pharmacol 11(2):209–215PubMedCrossRefGoogle Scholar
  2. Abernethy DR, Greenblatt DJ, Smith TW (1981) Digoxin disposition in obesity: clinical pharmacokinetic investigation. Am Heart J 102(4):740–744PubMedCrossRefGoogle Scholar
  3. Abernethy DR, Greenblatt DJ, Divoll M et al (1984) The influence of obesity on the pharmacokinetics of oral alprazolam and triazolam. Clin Pharmacokinet 9(2):177–183PubMedCrossRefGoogle Scholar
  4. Adane ED, Herald M, Koura F (2015) Pharmacokinetics of vancomycin in extremely obese patients with suspected or confirmed Staphylococcus aureus infections. Pharmacotherapy 35(2):127–139PubMedCrossRefGoogle Scholar
  5. Allard S, Kinzig M, Boivin G et al (1993) Intravenous ciprofloxacin disposition in obesity. Clin Pharmacol Ther 54(4):368–373PubMedCrossRefGoogle Scholar
  6. Alobaid AS, Hites M, Lipman J et al (2016) Effect of obesity on the pharmacokinetics of antimicrobials in critically ill patients: a structured review. Int J Antimicrob Agents 47(4):259–268PubMedCrossRefGoogle Scholar
  7. Alquwaizani M, Buckley L, Adams C, Fanikos J (2013) Anticoagulants: a review of the pharmacology, dosing, and complications. Curr Emerg Hosp Med Rep 1:83–97PubMedPubMedCentralCrossRefGoogle Scholar
  8. Anderson WJ, Lipworth BJ (2012) Does body mass index influence responsiveness to inhaled corticosteroids in persistent asthma? Ann Allergy Asthma Immunol 108(4):237–242PubMedCrossRefGoogle Scholar
  9. Atkinson AJ, Abernethy DR, Daniels CE, Dedrick RL, Markey SP (2007) Principles of clinical pharmacology, 2nd edn. Academic, AmsterdamGoogle Scholar
  10. Bauer LA, Drew Edwards WA, Patchen Dellinger E et al (1983) Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol 24:643–647PubMedCrossRefGoogle Scholar
  11. Beavers CJ, Heron P, Smyth SS et al (2015) Obesity and antiplatelets-does one size fit all? Thromb Res 136:712–716PubMedCrossRefGoogle Scholar
  12. Blouin RA, Warren GW (1999) Pharmacokinetic considerations in obesity. J Pharm Sci 88(1):1–7PubMedCrossRefGoogle Scholar
  13. Bordeaux BC, Qayyum R, Yanek LR et al (2010) Effect of obesity on platelet reactivity and response to low-dose aspirin. Prev Cardiol 13:56–62PubMedCrossRefGoogle Scholar
  14. Bowman SL, Hudson SA, Simpson G et al (1986) A comparison of the pharmacokinetics of propranolol in obese and normal volunteers. Br J Clin Pharmacol 21:529–532PubMedPubMedCentralCrossRefGoogle Scholar
  15. Brill MJ, Diepstraten J, van Rongen A et al (2012) Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet 51(5):277–304PubMedCrossRefGoogle Scholar
  16. Brill MJ, van Rongen A, Houwink AP et al (2014a) Midazolam pharmacokinetics in morbidly obese patients following semi-simultaneous oral and intravenous administration: a comparison with healthy volunteers. Clin Pharmacokinet 53:931–941PubMedPubMedCentralCrossRefGoogle Scholar
  17. Brill MJ, Houwink AP, Schmidt S et al (2014b) Reduced subcutaneous tissue distribution of cefazolin in morbidly obese versus non-obese patients determined using clinical microdialysis. J Antimicrob Chemother 69:715–723PubMedCrossRefGoogle Scholar
  18. Brunton LL, Lazo JS, Parker KL (eds) (2006) Goodman and Gilman’s The pharmacological basis of therapeutics, 11th edn. McGraw-Hill, New YorkGoogle Scholar
  19. Casati A, Putzu M (2005) Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth 17(2):134–145PubMedCrossRefGoogle Scholar
  20. Cataldi M, di Geronimo O, Trio R, Scotti A et al (2016) Utilization of antihypertensive drugs in obesity-related hypertension: a retrospective observational study in a cohort of patients from southern Italy. BMC Pharmacol Toxicol 17:9PubMedPubMedCentralCrossRefGoogle Scholar
  21. Cheymol G (2000) Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet 39(3):215–231PubMedCrossRefGoogle Scholar
  22. Cheymol G, Poirier J-M, Barre J, Pradalier A, Dry J (1987) Comparative pharmacokinetics of intravenous propranolol in obese and normal volunteers. J Clin Pharmacol 27(11):874–879PubMedCrossRefGoogle Scholar
  23. Cheymol G, Woestenborghs R, Snoeck E et al (1997) Pharmacokinetic study and cardiovascular monitoring of nebivolol in normal and obese subjects. Eur J Clin Pharmacol 51(6):493–498PubMedCrossRefGoogle Scholar
  24. Cho S-J, Yoon I-S, Kim D-D (2013) Obesity-related physiological changes and their pharmacokinetic consequences. J Pharm Investig 43:161–169CrossRefGoogle Scholar
  25. Christoff PB, Conti DR, Naylor C, Jusko WJ (1983) Procainamide disposition in obesity. Drug Intell Clin Pharm 17(7–8):516–522PubMedCrossRefGoogle Scholar
  26. de la Peña A, Yeo KP, Linnebjerg H et al (2015) Subcutaneous injection depth does not affect the pharmacokinetics or glucodynamics of insulin lispro in normal weight or healthy obese subjects. J Diabetes Sci Technol 9(4):824–830PubMedPubMedCentralCrossRefGoogle Scholar
  27. Dunn TE, Ludwig EA, Slaughter RL et al (1991) Pharmacokinetics and pharmacodynamics of methylprednisolone in obesity. Clin Pharmacol Ther 49(5):536–549PubMedCrossRefGoogle Scholar
  28. Dvorchik BH, Damphousse D (2005) The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched non-obese subjects. J Clin Pharmacol 45:48–56PubMedCrossRefGoogle Scholar
  29. Edelman AB, Cherala G, Blue SW et al (2016) Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing. Contraception 94(1):52–57PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fan J, de Lannoy IA (2014) Pharmacokinetics. Biochem Pharmacol 87:93–120PubMedCrossRefGoogle Scholar
  31. Farrell GC, Teoh N, McCuskey R (2008) Hepatic microcirculation in fatty liver disease. Anat Rec Adv Integr Anat Evol Biol 291(6):684–692CrossRefGoogle Scholar
  32. Freeman AL, Pendleton RC, Rondina MT (2010) Prevention of venous thromboembolism in obesity. Expert Rev Cardiovasc Ther 8(12):1711–1721PubMedPubMedCentralCrossRefGoogle Scholar
  33. Fukuchi H, Nakashima M, Araki R et al (2009) Effect of obesity on serum amiodarone concentration in Japanese patients: population pharmacokinetic investigation by multiple trough screen analysis. J Clin Pharm Ther 34(3):329–336PubMedCrossRefGoogle Scholar
  34. Galletti F, Fasano ML, Ferrara LA et al (1989) Obesity and beta-blockers: influence of body fat on their kinetics and cardiovascular effects. J Clin Pharmacol 29(3):212–216PubMedCrossRefGoogle Scholar
  35. Gandhi A, Moorthy B, Ghose R (2012) Drug disposition in pathophysiological conditions. Curr Drug Metab 13(9):1327–1344PubMedPubMedCentralCrossRefGoogle Scholar
  36. Glasier A (2013) Emergency contraception: clinical outcomes. Contraception 87(3):309–313PubMedCrossRefGoogle Scholar
  37. Glasier A, Cameron ST, Blithe D et al (2011) Can we identify women at risk of pregnancy despite using emergency contraception? Data from randomized trials of ulipristal acetate and levonorgestrel. Contraception 84(4):363–367PubMedCrossRefGoogle Scholar
  38. Hanley MJ, Abernethy DR, Greenblatt DJ (2010) Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 49(2):71–87PubMedCrossRefGoogle Scholar
  39. Hites M, Taccone FS, Wolff F et al (2014) Broad-spectrum β-lactams in obese non-critically ill patients. Nutr Diabetes 4(6):e119PubMedPubMedCentralCrossRefGoogle Scholar
  40. Jain R, Chung SM, Jain L et al (2011) Implications of obesity for drug therapy: limitations and challenges. Clin Pharmacol Ther 90(1):77–89PubMedCrossRefGoogle Scholar
  41. Jensen MD, Ryan DH, Apovian CM et al (2014) 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults. J Am Coll Cardiol 63:2985–3023PubMedCrossRefGoogle Scholar
  42. Jiang X-L, Samant S, Lesko LJ, Schmidt S (2015) Clinical pharmacokinetics and pharmacodynamics of clopidogrel. Clin Pharmacokinet 54:147–166PubMedPubMedCentralCrossRefGoogle Scholar
  43. Joy M, Tharp E, Hartman H et al (2016) Safety and efficacy of high-dose unfractionated heparin for prevention of venous thromboembolism in overweight and obese patients. Pharmacotherapy 36(7):740–748PubMedCrossRefGoogle Scholar
  44. Jusko WJ (2017) Clarification of contraceptive drug pharmacokinetics in obesity. Contraception 95:10–16PubMedCrossRefGoogle Scholar
  45. Kees MG, Weber S, Kees F, Horbach T (2011) Pharmacokinetics of moxifloxacin in plasma and tissue of morbidly obese patients. J Antimicrob Chemother 66:2330–2335PubMedCrossRefGoogle Scholar
  46. Knibbe CA, Brill MJ, van Rongen A et al (2015) Drug disposition in obesity: toward evidence-based dosing. Annu Rev Pharmacol Toxicol 55:149–167PubMedCrossRefGoogle Scholar
  47. Kubitza D, Becka M, Zuehlsdorf M, Mueck W (2007) Body weight has limited influence on the safety, tolerability, pharmacokinetics, pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 47:218PubMedCrossRefGoogle Scholar
  48. Landsberg L, Aronne LJ, Beilin LJ et al (2013) Obesity-related hypertension: pathogenesis, cardiovascular risk, and treatment. A position paper of the obesity society and the American Society of Hypertension. J Clin Hypertens (Greenwich) 15:14–33CrossRefGoogle Scholar
  49. Lentz SR (2016) Thrombosis in the setting of obesity or inflammatory bowel disease. Blood 128(20):2388–2394PubMedCrossRefGoogle Scholar
  50. Levy BI, Schiffrin EL, Mourad JJ et al (2008) Impaired tissue perfusion a pathology common to hypertension, obesity, and diabetes mellitus. Circulation 118(9):968–976PubMedCrossRefGoogle Scholar
  51. Leykin Y, Miotto L, Pellis T (2011) Pharmacokinetic considerations in the obese. Best Pract Res Clin Anaesthesiol 25:27–36PubMedCrossRefGoogle Scholar
  52. Martin JH, Saleem M, Looke D (2012) Therapeutic drug monitoring to adjust dosing in morbid obesity – a new use for an old methodology. Br J Clin Pharmacol 73(5):685–690PubMedCrossRefGoogle Scholar
  53. Michalaki MA, Gkotsina MI, Mamali I et al (2011) Impaired pharmacokinetics of levothyroxine in severely obese volunteers. Thyroid 21(5):477–481PubMedCrossRefGoogle Scholar
  54. Moine P, Mueller SW, Schoen JA et al (2016) Pharmacokinetic and pharmacodynamic evaluation of a weight-based dosing regimen of cefoxitin for perioperative surgical prophylaxis in obese and morbidly obese patients. Antimicrob Agents Chemother 60(10):5885–5893PubMedPubMedCentralCrossRefGoogle Scholar
  55. Mornar S, Chan LN, Mistretta S et al (2012) Pharmacokinetics of the etonogestrel contraceptive implant in obese women. Am J Obstet Gynecol 207(2):110.e1–110.e6CrossRefGoogle Scholar
  56. Morrish GA, Pai MP, Green B (2011) The effects of obesity on drug pharmacokinetics in humans. Expert Opin Drug Metab Toxicol 7(6):697–706PubMedCrossRefGoogle Scholar
  57. Mueck W, Stampfuss J, Kubitza D, Becka M (2014) Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 53:1–16PubMedCrossRefGoogle Scholar
  58. Munjal S, Gautam A, Rapoport AM, Fisher DM (2016) The effect of weight, body mass index, age, sex, and race on plasma concentrations of subcutaneous sumatriptan: a pooled analysis. Clin Pharmacol Adv Appl 8:109–116Google Scholar
  59. Reflection paper on investigation of pharmacokinetics and pharmacodynamics in the obese population 25 January 2018 1, EMA/CHMP/535116/2016 2, Committee for Human Medicinal Products (CHMP)Google Scholar
  60. Robinson JA, Burke AE (2013) Obesity and hormonal contraceptive efficacy. Women’s Health (Lond Engl) 9(5):453–466CrossRefGoogle Scholar
  61. Rowland M, Tozer TN (1995) Clinical pharmacokinetics, concepts and applications, 3rd edn. Lippincott Williams & Wilkins, PhiladelphiaGoogle Scholar
  62. Shah DK, Missmer SA, Correia KF, Ginsburg ES (2014) Pharmacokinetics of human chorionic gonadotropin injection in obese and normal-weight women. J Clin Endocrinol Metab 99(4):1314–1321PubMedPubMedCentralCrossRefGoogle Scholar
  63. Shank BR, Zimmerman DE (2015) Demystifying drug dosing in obese patients. American Society of Health System Pharmacists. eBookGoogle Scholar
  64. Simmons KB, Edelman AB (2016) Hormonal contraception and obesity. Fertil Steril 106(6):1282–1288PubMedCrossRefGoogle Scholar
  65. Smit C, De Hoogd S, Brüggemann RJM, Knibbe CAJ (2018) Obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. Expert Opin Drug Metab Toxicol 14(3):275–285PubMedCrossRefGoogle Scholar
  66. Steinkampf MP, Hammond KR, Nichols JE, Slayden SH (2003) Effect of obesity on recombinant follicle stimulating hormone absorption: subcutaneous versus intramuscular administration. Fertil Steril 80(1):99–102PubMedCrossRefGoogle Scholar
  67. Sturm AW, Allen N, Rafferty KD et al (2014) Pharmacokinetic analysis of piperacillin administered with tazobactam in critically ill, morbidly obese surgical patients. Pharmacotherapy 34(1):28–35PubMedCrossRefGoogle Scholar
  68. Thompson-Moore NR, Wanat MA, Putney DR et al (2015) Evaluation and pharmacokinetics of treatment dose enoxaparin in hospitalized patients with morbid obesity. Clin Appl Thromb Hemost 21(6):513–520PubMedCrossRefGoogle Scholar
  69. Tucker GT (1981) Measurement of the renal clearance of drugs. Br J Clin Pharmacol 12:761–770PubMedPubMedCentralCrossRefGoogle Scholar
  70. van Kralingen S, Diepstraten J, Peeters MY et al (2011) Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients. Clin Pharmacokinet 50:739–750PubMedCrossRefGoogle Scholar
  71. van Rongen A, Välitalo PAJ, Peeters MYM et al (2016) Morbidly obese patients exhibit increased CYP2E1-mediated oxidation of acetaminophen. Clin Pharmacokinet 55:833–847PubMedPubMedCentralCrossRefGoogle Scholar
  72. Wallace JL, Reaves AB, Tolley EA et al (2013) Comparison of initial warfarin response in obese patients versus non-obese patients. J Thromb Thrombolysis 36(1):96–101PubMedCrossRefGoogle Scholar
  73. Westhoff CL, Reinecke I, Bangerter K, Merz M (2014) Impact of body mass index on suppression of follicular development and ovulation using a transdermal patch containing 0.55-mg ethinyl estradiol/2.1-mg gestodene: a multicenter, open-label, uncontrolled study over three treatment cycles. Contraception 90(3):272–279PubMedCrossRefGoogle Scholar
  74. Wójcicki J, Jaroszynska M, Droździk M et al (2003) Comparative pharmacokinetics and pharmacodynamics of propranolol and atenolol in normolipaemic and hyperlipidaemic obese subjects. Biopharm Drug Dispos 24(5):211–218PubMedCrossRefGoogle Scholar
  75. World Health Organization (2018) Obesity and overweight. http://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 8 Oct 2018
  76. Wu B (2016) Morbid obesity alters both pharmacokinetics and pharmacodynamics of propofol: dosing recommendation for anesthesia induction (Short communication). Drug Metab Dispos 44:1579–1583PubMedCrossRefGoogle Scholar
  77. Zuckerman M, Greller HA, Babu KM (2015) A review of the toxicologic implications of obesity. J Med Toxicol 11:342–354PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Cardiovascular and Metabolism Medical AffairsJanssen Pharmaceuticals Inc.TitusvilleUSA

Personalised recommendations