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Applied Pharmacometrics in the Obese Population

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Applied Pharmacometrics

Part of the book series: AAPS Advances in the Pharmaceutical Sciences Series ((AAPS,volume 14))

Abstract

The pharmacokinetic (PK) and/or pharmacodynamic (PD) profile of drugs in obese individuals may be altered due to associated (patho)physiological changes, necessitating adapted dosing algorithms. Until recently, the obese population was hardly studied in pharmacometric analyses. The influence of obesity on PK and PD parameters has received more attention, given the strong rise in obesity incidence and prevalence across the world. In this review, an overview is given of obesity-related body size descriptors and reported equations quantifying obesity-related changes in population, PK and PD parameters, including how these equations were validated.

This chapter shows that many different size descriptors and other covariates in many different equations (linear or nonlinear) have been identified as predictors for the PK parameter clearance and volume of distribution, resulting in complex equations. For clearance, a decrease, increase or unchanged value was reported depending on the elimination pathway and studied population. Volume of distribution was found to increase or remained unchanged, although limited data were available to identify the influence of obesity on this parameter. Very few studies have been performed on the PD profile of drugs in obese patients. It can be concluded that more PK and PD studies in obesity are needed and that future models should be properly evaluated and validated. This chapter will raise important issues for the design of future studies and also the evaluation criteria for covariate modelling to avoid model misspecification.

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References

  • Bardin C, Nobecourt E, Larger E, Chast F, Treluyer JM, Urien S (2012) Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus. Eur J Clin Pharmacol 68(6):961–968

    Article  CAS  PubMed  Google Scholar 

  • Barras MA, Duffull SB, Atherton JJ, Green B (2009) Modelling the occurrence and severity of enoxaparin-induced bleeding and bruising events. Br J Clin Pharmacol 68(5):700–711

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barrett JS, Gibiansky E, Hull RD, Planes A, Pentikis H, Hainer JW et al (2001) Population pharmacodynamics in patients receiving tinzaparin for the prevention and treatment of deep vein thrombosis. Int J Clin Pharmacol Ther 39(10):431–446

    CAS  PubMed  Google Scholar 

  • Bauer LA, Edwards WA, Dellinger EP, Simonowitz DA (1983) Influence of weight on aminoglycoside pharmacokinetics in normal weight and morbidly obese patients. Eur J Clin Pharmacol 24(5):643–647

    Article  CAS  PubMed  Google Scholar 

  • Benezet S, Guimbaud R, Chatelut E, Chevreau C, Bugat R, Canal P (1997) How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients. Ann Oncol 8(6):607–609

    Article  CAS  PubMed  Google Scholar 

  • Brendel K, Comets E, Laffont C, Laveille C, Mentre F (2006) Metrics for external model evaluation with an application to the population pharmacokinetics of gliclazide. Pharm Res 23(9):2036–2049

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Brendel K, Dartois C, Comets E, Lemenuel-Diot A, Laveille C, Tranchand B et al (2007) Are population pharmacokinetic and/or pharmacodynamic models adequately evaluated? A survey of the literature from 2002 to 2004. Clin Pharmacokinet 46(3):221–234

    Article  PubMed Central  PubMed  Google Scholar 

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

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Cortinez LI, Anderson BJ, Penna A, Olivares L, Munoz HR, Holford NH et al (2010) Influence of obesity on propofol pharmacokinetics: derivation of a pharmacokinetic model. Br J Anaesth 105(4):448–456

    Article  CAS  PubMed  Google Scholar 

  • Cortinez LI, Gambus P, Troconiz IF, Echevarria G, Munoz HR (2011) Obesity does not influence the onset and offset of sevoflurane effect as measured by the hysteresis between sevoflurane concentration and bispectral index. Anesth Analg 113(1):70–76

    Article  CAS  PubMed  Google Scholar 

  • Devine J (1974) Gentamycin therapy. Ann Pharmacother 8:650–655

    Google Scholar 

  • Diepstraten J, Chidambaran V, Sadhasivam S et al (2012) Propofol clearance in morbidly obese children and adolescents: influence of age and body size. Clin Pharmacokinet 51(8):543–551

    Article  CAS  PubMed  Google Scholar 

  • DuBois D, DuBois EF (1916) A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 17:863–871

    Article  CAS  Google Scholar 

  • Egan TD (1995) Remifentanil pharmacokinetics and pharmacodynamics. A preliminary appraisal. Clin Pharmacokinet 29(2):80–94

    Article  CAS  PubMed  Google Scholar 

  • Egan TD, Huizinga B, Gupta SK, Jaarsma RL, Sperry RJ, Yee JB et al (1998) Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology 89(3):562–573

    Article  CAS  PubMed  Google Scholar 

  • Ekhart C, Rodenhuis S, Schellens JH, Beijnen JH, Huitema AD (2009) Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? Cancer Chemother Pharmacol 64(1):115–122

    Article  CAS  PubMed  Google Scholar 

  • Fukuchi H, Nakashima M, Araki R, Komiya N, Hayano M, Yano K 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):329–336

    Article  CAS  PubMed  Google Scholar 

  • Garrow JS, Webster J (1985) Quetelet’s index (W/H2) as a measureof fatness. Int J Obes 9:147–153

    CAS  PubMed  Google Scholar 

  • Green B, Duffull SB (2003) Development of a dosing strategy for enoxaparin in obese patients. Br J Clin Pharmacol 56(1):96–103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Green B, Duffull SB (2004) What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol 58(2):119–133

    Article  PubMed Central  PubMed  Google Scholar 

  • Hall RG, Swancutt MA, Gumbo T (2011) Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother 55(11):5107–5112

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hall RG 2nd, Swancutt MA, Meek C, Leff RD, Gumbo T (2012) Ethambutol pharmacokinetic variability is linked to body mass in overweight, obese, and extremely obese people. Antimicrob Agents Chemother 56(3):1502–1507

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Han PY, Duffull SB, Kirkpatrick CM, Green B (2007) Dosing in obesity: a simple solution to a big problem. Clin Pharmacol Ther 82(5):505–508

    Article  CAS  PubMed  Google Scholar 

  • Han PY, Kirkpatrick CM, Green B (2009) Informative study designs to identify true parameter-covariate relationships. J Pharmacokinet Pharmacodyn 36(2):147–163

    Article  PubMed  Google Scholar 

  • Holford NH (2005) The visual predictive check—superiority to standard diagnostic (Rorschach) plots. Population Approach Group in Europe, Pamplona, Spain. http://www.page-meeting.org/default.asp?abstract=738.

  • James W (1976) Research on Obesity. London: Her Majesty’s Stationery Office

    Google Scholar 

  • Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B (2005) Quantification of lean bodyweight. Clin Pharmacokinet 44(10):1051–1065

    Article  PubMed  Google Scholar 

  • Keys A, Fidanza F, Karvonen MJ, Kimura N, Taylor HL (1972) Indices of relative weight and obesity. J Chronic Dis 25(6):329–343

    Article  CAS  PubMed  Google Scholar 

  • Kotlyar M, Carson SW (1999) Effects of obesity on the cytochrome P450 enzyme system. Int J Clin Pharmacol Ther 37(1):8–19

    CAS  PubMed  Google Scholar 

  • Krekels EH, van Hasselt JG, Tibboel D, Danhof M, Knibbe CA (2011) Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models. Pharm Res 28(4):797–811

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lemmens HJ, Bernstein DP, Brodsky JB (2006) Estimating blood volume in obese and morbidly obese patients. Obes Surg 16(6):773–776

    Article  PubMed  Google Scholar 

  • Li XS, Nielsen J, Cirincione B, Li H, Addy C, Wagner J et al (2010) Development of a population pharmacokinetic model for taranabant, a cannibinoid-1 receptor inverse agonist. AAPS J 12(4):537–547

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lorentz F (1929) Ein neuer Konstitutionsindex. Klin Wochenschrift 8:348–351

    Article  Google Scholar 

  • Maric-Bilkan C (2013) Obesity and diabetic kidney disease. Med Clin North Am 97(1):59–74

    Article  PubMed Central  PubMed  Google Scholar 

  • Marik P, Varon J (1998) The obese patient in the ICU. Chest 113(2):492–498

    Article  CAS  PubMed  Google Scholar 

  • McLeay SC, Morrish GA, Kirkpatrick CM, Green B (2012) The relationship between drug clearance and body size: systematic review and meta-analysis of the literature published from 2000 to 2007. Clin Pharmacokinet 51(5):319–330

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Mosteller RD (1987) Simplified calculation of body-surface area. N Engl J Med 379:1098

    Google Scholar 

  • Nguyen L, Leger F, Lennon S, Puozzo C (2006) Intravenous busulfan in adults prior to haematopoietic stem cell transplantation: a population pharmacokinetic study. Cancer Chemother Pharmacol 57(2):191–198

    Article  CAS  PubMed  Google Scholar 

  • Pai MP, Lodise TP Jr (2011) Oseltamivir and oseltamivir carboxylate pharmacokinetics in obese adults: dose modification for weight is not necessary. Antimicrob Agents Chemother 55(12):5640–5645.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Peck CC, Murphy MG (1989) Bedside estimation of ideal body weight. Applied Therapeutics, Inc., Vancouver

    Google Scholar 

  • Rowland M, Tozer TN (1995) Clinical pharmacokinetics, concepts, and applications, 3rd edn. Williams and Wilkins, Baltimore

    Google Scholar 

  • Schmitt A, Gladieff L, Lansiaux A, Bobin-Dubigeon C, Etienne-Grimaldi MC, Boisdron-Celle M et al (2009) A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients. Clin Cancer Res 15(10):3633–3639

    Article  CAS  PubMed  Google Scholar 

  • Slepchenko G, Simon N, Goubaux B, Levron JC, Le Moing JP, Raucoules-Aime M (2003) Performance of target-controlled sufentanil infusion in obese patients. Anesthesiology 98(1):65–73

    Article  CAS  PubMed  Google Scholar 

  • Somogyi A, Stockley C, Keal J, Rolan P, Bochner F (1987) Reduction of metformin renal tubular secretion by cimetidine in man. Br J Clin Pharmacol 23(5):545–551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Stein PD, Matta F, Goldman J (2011) Obesity and pulmonary embolism: the mounting evidence of risk and the mortality paradox. Thromb Res 128(6):518–523

    Article  CAS  PubMed  Google Scholar 

  • Stone AA, Broderick JE (2012) Obesity and pain are associated in the United States. Obesity (Silver Spring) 20(7):1491–1495

    Article  Google Scholar 

  • Thomson AH, Staatz CE, Tobin CM, Gall M, Lovering AM (2009) Development and evaluation of vancomycin dosage guidelines designed to achieve new target concentrations. J Antimicrob Chemother 63(5):1050–1057

    Article  CAS  PubMed  Google Scholar 

  • van Kralingen S, Diepstraten J, Wiezer RJ et al (2011) Population pharmacokinetics and pharmacodynamics of propofol in morbidly obese patients. Clin Pharmacokinet 50(11):739–750

    Article  CAS  PubMed  Google Scholar 

  • Van Wart S, Phillips L, Bello A et al (2004) Population pharmacokinetics and pharmacodynamics of garenoxacin in patients with community-acquired respiratory tract infections. Antimicrob Agents Chemother 48(12):4766–4777

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wehrmeister FC, Menezes AM, Muniz LC, Martinez-Mesa J, Domingues MR, Horta BL (2012) Waist circumference and pulmonary function: a systematic review and meta-analysis. Syst Rev 1:55

    Article  PubMed Central  PubMed  Google Scholar 

  • World Health Organisation (1997) Obesity: preventing and managing the global epidemic. World Health Organisation, Geneva

    Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy, St. Antonius Hospital, P.O. Box 2500, 3430 EM, Nieuwegein, The Netherlands

    Anne van Rongen MSc, Margreke J. E. Brill MSc, Jeroen Diepstraten PhD & Catherijne A. J. Knibbe MD

Authors
  1. Anne van Rongen MSc
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  2. Margreke J. E. Brill MSc
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  3. Jeroen Diepstraten PhD
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  4. Catherijne A. J. Knibbe MD
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Corresponding author

Correspondence to Catherijne A. J. Knibbe MD .

Editor information

Editors and Affiliations

  1. University of Florida, Department of Pharmaceutics, Center for Pharmacometrics & Systems Pharmacology, Orlando, Florida, USA

    Stephan Schmidt

  2. University of Florida, College of Pharmacy, Department of Pharmaceutics, Gainesville, Florida, USA

    Hartmut Derendorf

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© 2014 American Association of Pharmaceutical Scientists

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van Rongen, A., Brill, M., Diepstraten, J., Knibbe, C. (2014). Applied Pharmacometrics in the Obese Population. In: Schmidt, S., Derendorf, H. (eds) Applied Pharmacometrics. AAPS Advances in the Pharmaceutical Sciences Series, vol 14. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1304-6_6

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