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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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Notes

Compliance with Ethical Standards

Funding

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)

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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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