Obesity-associated changes in drug pharmacokinetics

Česká verzia

Authors: Alena Pilková; Jan Miroslav Hartinger
Authors place of work: Farmakologický ústav 1. lékařské fakulty Univerzity Karlovy, Praha ; Oddělení klinické farmakologie a farmacie, Všeobecná fakultní nemocnice v Praze
Published in the journal: Vnitř Lék 2020; 66(8): 465-471
Category: Main Topic

Summary

Pharmacokinetics of drugs in obese patients can be affected by changes in drug distribution and/or changes in elimination functions. Drug dosing based on patient‘s weight or body surface area may not be satisfactory in terms of safety or efficacy, especially for patients with a higher degree of obesity. However, current knowledge about most drugs does not provide sufficient guidance for dose adjustment in this group of patients. This article provides an overview of factors influencing changes in pharmacokinetics of drugs in obese, including some examples (eg. analgesics, antibiotics, anticoagulants and others). Due to different changes in pharmacokinetics, which cannot always be estimated from the physical and chemical properties of drug molecular structure, it is important to assess pharmacokinetic properties of a particular drug rather than looking for general rules for the most appropriate dosing. In case of drugs with a narrow therapeutic index (aminoglycoside antibiotics and vancomycin, anticonvulsants, immunosuppressants, lithium, digoxin and theophylline), it is always advisable to measure drug plasma levels and use therapeutic drug monitoring.

Keywords:

dosing – pharmacokinetics – obesity – volume of distribution – dose adjustments – clearance

Zdroje

1. Cheymol G. Effects of obesity on pharmacokinetics implications for drug therapy. Clin Pharmacokinet, 2000; 39(3): 215–231.

2. Kunešová M. Obezita – etiopatogeneze, diagnostika a léčba. Interní medicína pro pra‑ xi, 2004; 9.

3. Platná SPC uváděných přípravků.

4. Hakim M, Anderson BJ, Walia H, et al. Acetaminophen pharmacokinetics in severely obe‑ se adolescents and young adults. Paediatr Anaesth, 2019; 29(1): 20–26.

5. van Rongen A, Välitalo PAJ, Peeters MYM, et al. Morbidly Obese Patients Exhibit Increased CY‑ P2E1-Mediated Oxidation of Acetaminophen. Clinical Pharmacokinetics, 2016; 55(7): 833–847.

6. Duffull SB, Dooley MJ, Green B, Poole SG, Kirkpatrick CM. A standard weight descriptor for dose adjustment in the obese patient. Clin Pharmacokinet, 2004; 43(15): 1167–1178.

7. Hanley MJ, Abernethy DR, Greenblatt DJ. Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet, 2010; 49(2): 71–87.

8. Heading RC, Nimmo J, Prescott LF, Tothill P. The dependence of paracetamol absorpti‑ on on the rate of gastric emptying. Br J Pharmacol, 1973; 47(2): 415–421.

9. Chan VO, Colville J, Persaud T, Buckley O, Hamilton S, Torreggiani WC. Intramuscular in‑ jections into the buttocks: are they truly intramuscular? Eur J Radiol, 2006; 58(3): 480–484.

10. Cockshott WP, Thompson GT, Howlett LJ, Seeley ET. Intramuscular or Intralipomatous Injections? New England Journal of Medicine, 1982; 307(6): 356–358.

11. De Hert M, Eramo A, Landsberg W, Kostic D, Tsai L‑F, Baker RA. Efficacy and safety of ari‑ piprazole once‑monthly in obese and nonobese patients with schizophrenia: a post hoc analysis. Neuropsychiatric disease and treatment, 2015; 11: 1299–1306.

12. Poland GA, Borrud A, Jacobson RM et al. Determination of deltoid fat pad thickness. Implications for needle length in adult immunization. Jama, 1997; 277(21): 1709–1711.

13. Cook IF, Williamson M, Pond D. Definition of needle length required for intramuscular deltoid injection in elderly adults: an ultrasonographic study. Vaccine, 2006; 24(7): 937–940.

14. Hollenstein UM, Brunner M, Schmid R, Müller M. Soft tissue concentrations of cipro‑ floxacin in obese and lean subjects following weight‑adjusted dosing. International Jour‑ nal of Obesity, 2001; 25(3): 354–358.

15. Bickel MH. Factors affecting the storage of drugs and other xenobiotics in adipose tissue. In: Advances in Drug Research. Testa, B, Meyer, UA (Eds.) 1994; 55–86.

16. Brill MJ, Diepstraten J, van Rongen A, van Kralingen S, van den Anker JN, Knibbe CA. Impact of obesity on drug metabolism and elimination in adults and children. Clin Pharmacokinet, 2012; 51(5): 277–304.

17. Abernethy DR, Greenblatt DJ, Divoll M, Smith RB, Shader RI. The Influence of Obesi‑ ty on the Pharmacokinetics of Oral Alprazolam and Triazolam. Clinical Pharmacokinetics, 1984; 9(2): 177–183.

18. Meng L, Mui E, Holubar MK, Deresinski SC. Comprehensive Guidance for Antibiotic Dosing in Obese Adults. Pharmacotherapy, 2017; 37(11): 1415–1431.

19. Bernstein RS, Thornton JC, Yang MU, et al. Prediction of the resting metabolic rate in obese patients. Am J Clin Nutr, 1983; 37(4): 595–602.

20. Abernethy DR, Greenblatt DJ, Smith TW. Digoxin disposition in obesity: clinical pharmacokinetic investigation. Am Heart J, 1981; 102(4): 740–744.

21. Lee LS, Chan LN. Evaluation of a sex‑based difference in the pharmacokinetics of digoxin. Pharmacotherapy, 2006; 26(1): 44–50.

22. Conway JM, Eberly LE, Collins JF et al. Factors in Variability of Serial Gabapentin Concentrations in Elderly Patients with Epilepsy. Pharmacotherapy, 2017; 37(10): 1197–1203.

23. Abernethy DR, Greenblatt DJ. Phenytoin disposition in obesity. Determination of loading dose. Arch Neurol, 1985; 42(5): 468–471.

24. Casati A, Putzu M. Anesthesia in the obese patient: pharmacokinetic considerations. J Clin Anesth, 2005; 17(2): 134–145.

25. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline. Journal of Clinical Oncology, 2012; 30(13): 1553–1561.

26. Morgan DJ, Bray KM. Lean body mass as a predictor of drug dosage. Implications for drug therapy. Clin Pharmacokinet, 1994; 26(4): 292–307.

27. Andrews LM, de Winter BC, Tang JT, et al. Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight‑Based Tacrolimus Starting Dose. Transplant Direct, 2017; 3(2), e129.

28. Rocca B, Fox KAA, Ajjan RA, et al. Antithrombotic therapy and body mass: an expert position paper of the ESC Working Group on Thrombosis. Eur Heart J, 2018; 39(19):1672–1686f.

29. Abernethy DR, Greenblatt DJ, Divoll M, Shader RI. Enhanced glucuronide conjugation of drugs in obesity: studies of lorazepam, oxazepam, and acetaminophen. J Lab Clin Med, 1983; 101(6): 873–880.

30. de Hoogd S, Välitalo PAJ, Dahan A, et al. Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide. Clinical pharmacokinetics, 2017; 56(12): 1577–1587.

31. Anastasio P, Spitali L, Frangiosa A, et al. Glomerular filtration rate in severely overweight normotensive humans. Am J Kidney Dis, 2000; 35(6): 1144–1148.

32. Winter MA, Guhr KN, Berg GM. Impact of various body weights and serum creatinine concentrations on the bias and accuracy of the Cockcroft‑Gault equation. Pharmacothe‑ rapy, 2012; 32(7): 604–612.

33. Abernethy DR, Divoll M, Greenblatt DJ, Ameer B. Obesity, sex, and acetaminophen disposition. Clin Pharmacol Ther, 1982; 31(6): 783–790.

34. Lee WH, Kramer WG, Granville GE. The effect of obesity on acetaminophen pharmacokinetics in man. J Clin Pharmacol, 1981; 21(7): 284–287.

35. Abernethy DR, Greenblatt DJ. Ibuprofen disposition in obese individuals. Arthritis Rheum, 1985; 28(10): 1117–1121.

36. Andersen G, Christrup L, Sjøgren P. Relationships Among Morphine Metabolism, Pain and Side Effects During Long‑Term Treatment: An Update. Journal of Pain and Symptom Management, 2003; 25(1): 74–91.

37. Patanwala AE, Holmes KL, Erstad BL. Analgesic response to morphine in obese and morbidly obese patients in the emergency department. Emerg Med J, 2014; 31(2): 139–142.

38. Schug SA, Raymann A. Postoperative pain management of the obese patient. Best Pract Res Clin Anaesthesiol, 2011; 25(1): 73–81.

39. Halilovic J, Heintz BH, Brown J. Risk factors for clinical failure in patients hospitalized with cellulitis and cutaneous abscess. J Infect, 2012; 65(2): 128–134.

40. Janson B, Thursky K. Dosing of antibiotics in obesity. Curr Opin Infect Dis, 2012; 25(6): 634–649.

41. Bouazza N, Pestre V, Jullien V, et al. Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis. Br J Clin Pharmacol, 2012; 74(6): 971–977.

42. Al‑Dorzi HM, Al Harbi SA, Arabi YM. Antibiotic therapy of pneumonia in the obese pa‑ tient: dosing and delivery. Curr Opin Infect Dis, 2014; 27(2): 165–173.

43. Bratzler DW, Dellinger EP, Olsen KM et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm, 2013; 70(3): 195–283.

44. Hussain Z, Curtain C, Mirkazemi C, Gadd K, Peterson GM, Zaidi STR. Prophylactic Cefazolin Dosing and Surgical Site Infections: Does the Dose Matter in Obese Patients? Obes Surg, 2019; 29(1): 159–165.

45. Hartinger J. Klinické aspekty aspirinové rezistence. (Remedia, 2017) 182–186

46. Tellor KB, Nguyen SN, Bultas AC, Armbruster AL, Greenwald NA, Yancey AM. Evaluation of the impact of body mass index on warfarin requirements in hospitalized patients. Ther Adv Cardiovasc Dis, 2018; 12(8): 207–216.

47. Wallace JL, Reaves AB, Tolley EA, et al. Comparison of initial warfarin response in obese patients versus non‑obese patients. J Thromb Thrombolysis, 2013; 36(1): 96–101.

48. Kido K, Lee JC, Hellwig T, Gulseth MP. Use of Direct Oral Anticoagulants in Morbidly Obese Patients. Pharmacotherapy, 2020; 40(1): 72–83.

49. Vandiver JW, Ritz LI, Lalama JT. Chemical prophylaxis to prevent venous thrombo‑ embolism in morbid obesity: literature review and dosing recommendations. J Thromb Thrombolysis, 2016; 41(3): 475–481.

50. Abernethy DR, Greenblatt DJ, Divoll M, Shader RI. Prolonged accumulation of diaze‑ pam in obesity. J Clin Pharmacol, 1983; 23(8–9): 369–376.