Optimizing Estimated Glomerular Filtration Rate to Support Adult to Pediatric Pharmacokinetic Bridging Studies in Patients with Cystic Fibrosis

  • Ryan L. Crass
  • Manjunath P. PaiEmail author
Original Research Article



The estimated glomerular filtration rate (eGFR) is often used to model drug clearance (CL) and scale doses across age and body size. Over their lifetime, patients with cystic fibrosis (CF) receive repeated courses of tobramycin, an antibiotic with eGFR-dependent CL, for the treatment of pulmonary exacerbations. Tobramycin population pharmacokinetic (PK) modeling can be used to decipher the best approach to define eGFR for pediatric bridging studies.


Inpatients with CF who received intravenous tobramycin between 1 January 2006 and 30 May 2018 were eligible for inclusion. Encounters without tobramycin concentration measurement or missing covariate data were excluded. Population PK analysis was performed using NONMEM.Covariate models were built  following identification of the base model, with specific emphasis on the effect of different methods of estimating renal function as a covariate of tobramycin CL.


A total of 296 CF patients contributed 1029 care encounters (420 pediatric, 609 adult) and 4352 tobramycin concentrations to this analysis. The median (minimum, maximum) age at encounter was 19 years (0.2, 60), with serum creatinine of 0.60 mg/dL (0.10, 3.41). A two-compartment model best described the observed data, with height and eGFR as significant covariates of tobramycin CL. eGFR was best modeled using a combination of the modified Schwartz and Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equations expressed in absolute units.


The CKDEPI equation bridges PK data generated in adults to adolescents with CF better than the current regulatory standard. The eGFR should be expressed in absolute units (mL/min) for PK analyses.


Compliance with Ethical Standards


This work was supported in part by start-up funds from the University of Michigan College of Pharmacy to MPP.

Conflicts of interest

Ryan L. Crass and Manjunath P. Pai have no potential conflicts of interest that might be relevant to this work.

Supplementary material

40262_2019_761_MOESM1_ESM.pdf (2.4 mb)
Supplementary material 1 (PDF 2460 kb)


  1. 1.
    Mahmood I. Dosing in children: a critical review of the pharmacokinetic allometric scaling and modelling approaches in paediatric drug development and clinical settings. Clin Pharmacokinet. 2014;53(4):327–46.CrossRefGoogle Scholar
  2. 2.
    Cella M, Knibbe C, Danhof M, Della Pasqua O. What is the right dose for children? Br J Clin Pharmacol. 2010;70(4):597–603.CrossRefGoogle Scholar
  3. 3.
    Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25–36.CrossRefGoogle Scholar
  4. 4.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE. Developmental pharmacology: drug disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157–67.CrossRefGoogle Scholar
  5. 5.
    Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.CrossRefGoogle Scholar
  6. 6.
    Levey AS, Inker LA. Assessment of glomerular filtration rate in health and disease: a state of the art review. Clin Pharmacol Ther. 2017;102(3):405–19.CrossRefGoogle Scholar
  7. 7.
    Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, et al. Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med. 2009;180(9):802–8.CrossRefGoogle Scholar
  8. 8.
    Levy J, Smith AL, Koup JR, Williams-Warren J, Ramsey B. Disposition of tobramycin in patients with cystic fibrosis: a prospective controlled study. J Pediatr. 1984;105(1):117–24.CrossRefGoogle Scholar
  9. 9.
    Delattre IK, Musuamba FT, Verbeeck RK, Dugernier T, Spapen H, Laterre PF, et al. Empirical models for dosage optimization of four beta-lactams in critically ill septic patients based on therapeutic drug monitoring of amikacin. Clin Biochem. 2010;43(6):589–98.CrossRefGoogle Scholar
  10. 10.
    Delattre IK, Musuamba FT, Jacqmin P, Taccone FS, Laterre PF, Verbeeck RK, et al. Population pharmacokinetics of four beta-lactams in critically ill septic patients comedicated with amikacin. Clin Biochem. 2012;45(10–11):780–6.CrossRefGoogle Scholar
  11. 11.
    Crass RL, Pai MP, Lodise TP Jr. Individualizing piperacillin/tazobactam dosing in adult patients with cystic fibrosis: can tobramycin measurements help? J Antimicrob Chemother. 2019;75(1):126–9.CrossRefGoogle Scholar
  12. 12.
    Koren G, James A, Perlman M. A simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn. Clin Pharmacol Ther. 1985;38(6):680–5.CrossRefGoogle Scholar
  13. 13.
    US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). General clinical pharmacology considerations for pediatric studies for drugs and biological products: guidance for industry; 2014. Accessed Mar 2019.
  14. 14.
    R Core Team (2017). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna.
  15. 15.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31–41.CrossRefGoogle Scholar
  16. 16.
    Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 1976;58(2):259–63.Google Scholar
  17. 17.
    Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr. 1984;104(6):849–54.CrossRefGoogle Scholar
  18. 18.
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–12.CrossRefGoogle Scholar
  19. 19.
    Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247–54.CrossRefGoogle Scholar
  20. 20.
    Selistre L, De Souza V, Cochat P, Antonello IC, Hadj-Aissa A, Ranchin B, et al. GFR estimation in adolescents and young adults. J Am Soc Nephrol. 2012;23(6):989–96.CrossRefGoogle Scholar
  21. 21.
    Selistre L, Rabilloud M, Cochat P, de Souza V, Iwaz J, Lemoine S, et al. Comparison of the Schwartz and CKD-EPI Equations for estimating glomerular filtration rate in children, adolescents, and adults: a retrospective cross-sectional study. PLoS Med. 2016;13(3):e1001979.CrossRefGoogle Scholar
  22. 22.
    Scaparrotta A, Di Pillo S, Attanasi M, Consilvio NP, Cingolani A, Rapino D, et al. Growth failure in children with cystic fibrosis. J Pediatr Endocrinol Metab. 2012;25(5–6):393–405.Google Scholar
  23. 23.
    Rey E, Treluyer JM, Pons G. Drug disposition in cystic fibrosis. Clin Pharmacokinet. 1998;35(4):313–29.CrossRefGoogle Scholar
  24. 24.
    Morison S, Dodge JA, Cole TJ, Lewis PA, Coles EC, Geddes D, et al. Height and weight in cystic fibrosis: a cross sectional study. UK Cystic Fibrosis Survey Management Committee. Arch Dis Child. 1997;77(6):497–500.CrossRefGoogle Scholar
  25. 25.
    Bilbao-Meseguer I, Rodriguez-Gascon A, Barrasa H, Isla A, Solinis MA. Augmented renal clearance in critically ill patients: a systematic review. Clin Pharmacokinet. 2018;57(9):1107–21.CrossRefGoogle Scholar
  26. 26.
    US Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: pharmacokinetics in patients with impaired renal function - study design, data analysis, and impact on dosing and labeling; 2010. Accessed 9 May 2018.
  27. 27.
    Town DJ, Vinks AA, Jacobs F, Heijerman HG, Bakker W. Creatinine clearance as predictor of tobramycin elimination in adult patients with cystic fibrosis. Ther Drug Monit. 1996;18(5):562–9.CrossRefGoogle Scholar
  28. 28.
    Halacova M, Kotaska K, Kukacka J, Vavrova V, Kuzelova M, Ticha J, et al. Serum cystatin C level for better assessment of glomerular filtration rate in cystic fibrosis patients treated by amikacin. J Clin Pharm Ther. 2008;33(4):409–17.CrossRefGoogle Scholar
  29. 29.
    Beringer PM, Hidayat L, Heed A, Zheng L, Owens H, Benitez D, et al. GFR estimates using cystatin C are superior to serum creatinine in adult patients with cystic fibrosis. J Cyst Fibros. 2009;8(1):19–25.CrossRefGoogle Scholar
  30. 30.
    Soulsby N, Greville H, Coulthard K, Doecke C. What is the best method for measuring renal function in adults and children with cystic fibrosis? J Cyst Fibros. 2010;9(2):124–9.CrossRefGoogle Scholar
  31. 31.
    Touw DJ, Vinks AA, Heijerman HG, Bakker W. Validation of tobramycin monitoring in adolescent and adult patients with cystic fibrosis. Ther Drug Monit. 1993;15(1):52–9.CrossRefGoogle Scholar
  32. 32.
    Alghanem S, Paterson I, Touw DJ, Thomson AH. Influence of multiple courses of therapy on aminoglycoside clearance in adult patients with cystic fibrosis. J Antimicrob Chemother. 2013;68(6):1338–47.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical Pharmacy, College of PharmacyUniversity of MichiganAnn ArborUSA

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