ALTERED PHARMACOKINETICS AND DRUG DOSING IN OBESE PATIENTS: A TRADITIONAL REVIEW

Öz

Objective: Obesity, with its growing global prevalence, is recognized as a significant risk factor for chronic diseases such as diabetes, dyslipidemia, and certain cancers. It also increases the risk of infections like bacteremia, surgical site infections, and soft tissue infections, thereby raising morbidity and mortality. In obese individuals, both adipose and muscle mass increase, but adipose tissue expands disproportionately, altering the volume of distribution (V_d) of drugs. This necessitates using specific body weight descriptors—ideal, total, adjusted, or lean body weight—for accurate dosing. No single descriptor suits all drugs; dosing should be drug-specific. For example, using ideal body weight for lipophilic drugs with a large V_d may lead to subtherapeutic levels, while using total body weight for hydrophilic drugs with a small V_d may cause toxicity. Obesity also alters hepatic and renal functions, impacting drug metabolism and clearance. These changes mainly affect drugs with high hydrophilicity or lipophilicity, notably antimicrobials and sedative-analgesics.

Result and Discussion: This review discusses current evidence on pharmacokinetic alterations in obese patients and provides guidance on selecting appropriate weight descriptors to ensure optimal dosing in this population.

Anahtar Kelimeler

• Drug
• infections
• metabolism
• obesity
• pharmacokinetics

OBEZ HASTALARDA DEĞİŞEN FARMAKOKİNETİK VE İLAÇ DOZLAMI: GELENEKSEL DERLEME

Öz

Amaç: Obezite, diyabet, dislipidemi ve bazı kanser türleri gibi kronik hastalıklar için dünya genelinde yaygınlaşan önemli bir risk faktörüdür. Ayrıca obezite, bakteriyemi, cerrahi enfeksiyonlar ve yumuşak doku enfeksiyonları gibi komplikasyon riskini artırmakta, morbidite ve mortalite oranını yükseltmektedir. Obez bireylerde yağ ve kas dokusu, obez olmayan hastalara göre artış göstermektedir ancak yağ dokusundaki artış orantısal olarak daha fazladır. Bu durum, ilaçların dağılım hacmini (DH) değiştirerek ideal, total, ayarlanmış veya yağsız vücut ağırlığı gibi farklı vücut ağırlığı tanımlarının kullanılmasını gerektirmektedir. Ancak tüm ilaçlar için evrensel olarak geçerli bir tanım yoktur; dozlama ilaçlar özelinde belirlenmelidir. Örneğin, büyük DH’ye sahip lipofilik bir ilacın dozunun ideal vücut ağırlığına göre hesaplanması yetersiz kan düzeyine, hidrofilik bir ilacın dozunun gerçek vücut ağırlığına göre hesaplanması ise toksisiteye yol açabilmektedir. Ayrıca obezitenin karaciğer ve böbrek fonksiyonlarını değiştirmesi, ilaç metabolizması ve klirensini etkilemektedir. Bu farmakokinetik değişikliklerden en çok antimikrobiyaller ve sedatif-analjezik ilaçlar etkilenmektedir.

Sonuç ve Tartışma: Bu derleme, obez hastalarda ilaç dozlamasını optimize etmek için en uygun vücut ağırlığı tanımının belirlenmesine yönelik güncel kanıtlara dayalı bilgiler sunmayı amaçlamaktadır.

Anahtar Kelimeler

• Enfeksiyonlar
• farmakokinetik
• ilaç
• metabolizma
• obezite

Kaynakça

1. 1. Obesity and overweight website (2024). https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed date: 08.12.2024.
2. 2. Stanton, R.A. (2006). Nutrition problems in an obesogenic environment. Medical Journal of Australia, 184(2), 76-79. [CrossRef]
3. 3. Schwartz, M.W., Seeley, R.J., Zeltser, L.M., et al. (2017). Obesity pathogenesis: An endocrine society scientific statement. Endocrine Reviews, 38(4), 267-296. [CrossRef]
4. 4. Türkiye İstatistik Kurumu (TÜİK) website (2024). https://www.tuik.gov.tr/. Accessed date: 08.12.2024.
5. 5. World Obesity Federation website (2023). https://www.worldobesity.org/resources/resource-library/world-obesity-atlas-2023. Accessed date: 08.12.2024.
6. 6. Huttunen, R., Syrjänen, J. (2012). Obesity and the risk and outcome of infection. International Journal of Obesity, 37(3), 333-340. [CrossRef]
7. 7. Meng, L., Mui, E., Ha, D.R., et al. (2023). Comprehensive guidance for antibiotic dosing in obese adults: 2022 update. Pharmacotherapy, 43(3), 226-246. [CrossRef]
8. 8. Fernandez, E., Perez, R., Hernandez, A., et al. (2011). Factors and mechanisms for pharmacokinetic differences between pediatrie population and adults. Pharmaceutics, 3(1), 53-72. [CrossRef]

9. 9. Bahap, M., Ekinci, P.B., Ekincioğlu, A.B., et al. (2020). Obez hastalarda antimikrobiyal ilaç dozları. Sürekli Tıp Eğitimi Dergisi, 29(2), 381-442. [CrossRef]
10. 10. Teixeira, T.F.S., Collado, M.C., Ferreira, C.L.L.F., et al. (2012). Potential mechanisms for the emerging link between obesity and increased intestinal permeability. Nutrition Research, 32(9), 637-647. [CrossRef]
11. 11. Cardoso-Junior, A., Coelho, L.G.V., Savassi-Rocha, P.R., et al. (2007). Gastric emptying of solids and semi-solids in morbidly obese and non-obese subjects: An assessment using the 13C-octanoic acid and 13C-acetic acid breath tests. Obesity Surgery, 17(2), 236-241. [CrossRef]
12. 12. Xing, J., Chen, J.D.Z. (2012). Alterations of gastrointestinal motility in obesity. Obesity Research, 12(11), 1723-1732. [CrossRef]
13. 13. Gouju, J., Legeay, S. (2023). Pharmacokinetics of obese adults: Not only an increase in weight. Biomedicine and Pharmacotherapy, 166, 115281. [CrossRef]
14. 14. Barras, M., Legg, A. (2017). Drug dosing in obese adults. Australian Prescriber, 40(5), 189-193. [CrossRef]
15. 15. Sampson, M.R., Cohen-Wolkowiez, M., Benjamin, D.K., et al. (2013). Pharmacokinetics of antimicrobials in obese children. Generics and Biosimilars Initiative Journal, 2(2), 76-81. [CrossRef]
16. 16. de Divitiis, O., Fazio, S., Petitto, M., et al. (1981). Obesity and cardiac function. Circulation, 64(3), 477-482. [CrossRef]
17. 17. Meng, L., Mui, E., Holubar, M.K., et al. (2017). Comprehensive guidance for antibiotic dosing in obese adults. Pharmacotherapy, 37(11), 1415-1431. [CrossRef]
18. 18. Cheymol, G. (2002). Effects of obesity on pharmacokinetics implications for drug therapy. Clinical Pharmacokinetics, 39(3), 215-231. [CrossRef]
19. 19. Hanley, M.J., Abernethy, D.R., Greenblatt, D.J. (2010). Effect of obesity on the pharmacokinetics of drugs in humans. Clinical Pharmacokinetics, 49(2), 71-87. [CrossRef]
20. 20. Brunt, E.M. (2004). Nonalcoholic steatohepatitis. Seminars in Liver Disease, 24(1), 3-20. [CrossRef]
21. 21. Blouin, R.A., Warren, G.W. (1999). Pharmacokinetic considerations in obesity. Journal of Pharmaceutical Sciences, 88(1), 1-7. [CrossRef]
22. 22. Chagnac, A., Herman, M., Zingerman, B., et al. (2008). Obesity-induced glomerular hyperfiltration: Its involvement in the pathogenesis of tubular sodium reabsorption. Nephrology Dialysis Transplantation, 23(12), 3946-3952. [CrossRef]
23. 23. Pai, M.P., Bearden, D.T. (2012). Antimicrobial dosing considerations in obese adult patients. Pharmacotherapy, 27(8), 1081-1091. [CrossRef]
24. 24. Mosteller, R.D. (1987). Simplified calculation of body-surface area. New England Journal of Medicine, 317(17), 1098-1098. [CrossRef]
25. 25. Counts, G.W., Blair, A.D., Wagner, K.F., et al. (1982). Gentamicin and tobramycin kinetics. Clinical Pharmacology and Therapeutics, 31(5), 662-668. [CrossRef]
26. 26. Castro-Balado, A., Varela-Rey, I., Mejuto, B., et al. (2024). Updated antimicrobial dosing recommendations for obese patients. Antimicrobial Agents and Chemotherapy, 68(5), e01719-23. [CrossRef]
27. 27. Velissaris, D., Karamouzos, V., Marangos, M., et al. (2014). Pharmacokinetic changes and dosing modification of aminoglycosides in critically ill obese patients: A literature review. Journal of Clinical Medicine Research, 6(4), 227-233. [CrossRef]
28. 28. Bouquegneau, A., Vidal-Petiot, E., Moranne, O., et al. (2015). Creatinine‐based equations for the adjustment of drug dosage in an obese population. British Journal of Clinical Pharmacology, 81(2), 349-361. [CrossRef]
29. 29. Lee, N., Patel, P., Nguyen, H. (2024). Ethambutol, StatPearls Publishing, Treasure Island (FL).
30. 30. Nahid, P., Dorman, S.E., Alipanah, N., et al. (2016). Official American Thoracic Society/Centers for disease control and prevention/Infectious Diseases Society of America clinical practice guidelines: Treatment of drug-susceptible tuberculosis. Clinical Infectious Diseases, 63(7), e147-195. [CrossRef]
31. 31. Hall, R.G., Swancutt, M.A., Meek, C., et al. (2012). Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people. Antimicrobial Agents Chemotherapy, 56(3), 1502-1507. [CrossRef]
32. 32. Hall II, R.G. (2015). Evolving larger: Dosing anti-tuberculosis drugs in an obese world. Current Pharmaceutical Design, 21(32), 4748-4751. [CrossRef]
33. 33. Donald, P.R., Maritz, J.S., Diacon, A.H. (2012). Pyrazinamide pharmacokinetics and efficacy in adults and children. Tuberculosis, 92(1), 1-8. [CrossRef]
34. 34. Robert Blum, M., Liaq, S.H.T., de Miranda, P. (1982). Overview of acyclovir pharmacokinetic disposition in adults and children. The American Journal of Medicine, 73(1), 186-192. [CrossRef]
35. 35. Seedat, A., Winnett, G. (2012). Acyclovir-induced acute renal failure and the importance of an expanding waist line. BMJ Case Reports, bcr2012006264. [CrossRef]
36. 36. Hernandez, J.O., Norstrom, J., Wysock, G. (2009). Acyclovir-induced renal failure in an obese patient. American Journal of Health-System Pharmacy, 66(14), 1288-1291. [CrossRef]
37. 37. Barber, K.E., Wagner, J.L., Stover, K.R. (2019). Impact of obesity on acyclovir-induced nephrotoxicity. Open Forum Infectious Diseases, 6(4), ofz121. [CrossRef]
38. 38. Turner, R.B., Cumpston, A., Sweet, M., et al. (2016). Prospective, controlled study of acyclovir pharmacokinetics in obese patients. Antimicrobial Agents and Chemotherapy, 60(3), 1830-1833. [CrossRef]
39. 39. Ye, L., You, X., Zhou, J., et al. (2022). Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment. Frontiers in Pharmacology, 13, 838599. [CrossRef]
40. 40. Bhavnani, S.M., Rubino, C.M., Ambrose, P.G., et al. (2010). Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: Data from a randomized trial of patients with bacteremia and endocarditis. Clinical Infectious Diseases, 50(12), 1568-1574. [CrossRef]
41. 41. Fox, A.N., Smith, W.J., Kupiec, K.E., et al. (2019). Daptomycin dosing in obese patients: Analysis of the use of adjusted body weight versus actual body weight. Therapeutic Advances in Infectious Disesase, 6. [CrossRef]
42. 42. Falcone, M., Russo, A., Venditti, M., et al. (2013). Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia. Clinical Infectious Diseases, 57(11), 1568-1576. [CrossRef]
43. 43. Britt, N.S., Potter, E.M., Patel, N., et al. (2017). Comparative effectiveness and safety of standard, medium, and high-dose daptomycin strategies for the treatment of vancomycin-resistant enterococcal bacteremia among Veterans Affairs patients. Clinical Infectious Diseases, 64(5), 605-613. [CrossRef]
44. 44. Wasmann, R.E., Smit, C., van Dongen, E.P.H., et al. (2020). Fixed dosing of liposomal amphotericin B in morbidly obese individuals. Clinical Infectious Diseases, 70(10), 2213-2215. [CrossRef]
45. 45. Amsden, J.R., Slain, D. (2011). Antifungal dosing in obesity: A review of the literature. Current Fungal Infectious Reports, 5(2), 83-91. [CrossRef]
46. 46. Shatri, G., Tadi, P. (2024). Polymyxin, StatPearls Publishing, Treasure Island (FL).
47. 47. Kassamali, Z., Jain, R., Danziger, L.H. (2015). An update on the arsenal for multidrug-resistant Acinetobacter infections: Polymyxin antibiotics. International Journal of Infectious Diseases, 30, 125-132. [CrossRef]
48. 48. Pai, M.P. (2013). Polymyxin B dosing in obese and underweight adults. Clinical Infectious Diseases, 57(12), 1785. [CrossRef]
49. 49. Pai, M.P. (2021). Antimicrobial dosing in specific populations and novel clinical methodologies: Obesity. Clinical Pharmacology and Therapeutics, 109(4), 942-951. [CrossRef]
50. 50. Gu, Q., Jones, N., Drennan, P., et al. (2022). Assessment of an institutional guideline for vancomycin dosing and identification of predictive factors associated with dose and drug trough levels. Journal of Infection, 85(4), 382-389. [CrossRef]
51. 51. Rybak, M.J., Le, J., Lodise, T.P., et al. (2020). Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections: A revised consensus guideline and review by the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the Society of Infectious Diseases Pharmacists. American Journal of Health-System Pharmacy, 77(11), 835-863. [CrossRef]
52. 52. Johnston, A. (2003). The pharmacokinetics of voriconazole. British Journal of Clinical Pharmacology, 56(s1), 1. [CrossRef]
53. 53. Davies-Vorbrodt, S., Ito, J.I., Tegtmeier, B.R., et al. (2013). Voriconazole serum concentrations in obese and overweight immunocompromised patients: A retrospective review. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 33(1), 22-30. [CrossRef]
54. 54. Koselke, E., Kraft, S., Smith, J., et al. (2012). Evaluation of the effect of obesity on voriconazole serum concentrations. Journal of Antimicrobial Chemotherapy, 67(12), 2957-2962. [CrossRef]
55. 55. Dickmeyer, N.J., Kiel, P.J. (2011). Dosing voriconazole in an obese patient. Clinical Infectious Diseases, 53(7), 745. [CrossRef]
56. 56. Wagner, B., O’Hara, D.A. (1997). Pharmacokinetics and pharmacodynamics of sedatives and analgesics in the treatment of agitated critically ill patients. Clinical Pharmacokinetics, 33(6), 426-453. [CrossRef]
57. 57. Marik, P.E. (2010). Management of the Critically Ill Geriatric Patient, Surgical Intensive Care Medicine, Springer, Boston, MA, 647-657.
58. 58. Pentel, P., Benowitz, N. (1984). Pharmacokinetic and pharmacodynamic considerations in drug therapy of cardiac emergencies. Clinical Pharmacokinetics, 9(4), 273-308. [CrossRef]
59. 59. Weerink, M.A.S., Struys, M.M.R.F., Hannivoort, L.N., et al. (2017). Clinical pharmacokinetics and pharmacodynamics of dexmedetomidine. Clinical Pharmacokinetics, 56(8), 893-913. [CrossRef]
60. 60. Atyia, S.A., Smetana, K.S., Tong, M.C., et al. (2021). Evaluation of dexmedetomidine dosing in obese critically ill patients. Journal of Pharmacy Practice, 36(1), 67-73. [CrossRef]
61. 61. Cortínez, L.I., Anderson, B.J., Holford, N.H.G., et al. (2015). Dexmedetomidine pharmacokinetics in the obese. European Journal of Clinical Pharmacology, 71(12), 1501-1508. [CrossRef]
62. 62. Greenblatt, D.J., Abernethy, D.R., Locniskar, A., et al. (1984). Effect of age, gender, and obesity on midazolam kinetics. Anesthesiology, 61(1), 27-35.
63. 63. Erstad, B.L., Barletta, J.F. (2020). Drug dosing in the critically ill obese patient-a focus on sedation, analgesia, and delirium. Critical Care, 24(1), 315. [CrossRef]
64. 64. Servin, F., Farinotti, R., Haberer, J.P., et al. (1993). Propofol infusion for maintenance of anesthesia in morbidly obese patients receiving nitrous oxide. A clinical and pharmacokinetic study. Anesthesiology, 78(4), 657-665. [CrossRef]
65. 65. Dong, D., Peng, X., Liu, J., et al. (2016). Morbid obesity alters both pharmacokinetics and pharmacodynamics of propofol: Dosing recommendation for anesthesia induction. Drug Metabolism Disposition, 44(10), 1579-1583. [CrossRef]
66. 66. Barletta, J. (2020). Drug dosing in special populations: Obesity and geriatrics, Issues in Critical Care Practice, CCSAP 2020, Lenexa, Kansas, 7-16.
67. 67. Egan, T.D., Huizinga, B., Gupta, S.K., et al. (1998). Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology, 89(3), 562-573. [CrossRef]