Journal of Antimicrobial Chemotherapy Advance Access published September 1, 2016

J Antimicrob Chemother
doi:10.1093/jac/dkw351

Urinary kidney injury biomarkers and tobramycin clearance among
children and young adults with cystic fibrosis: a population
pharmacokinetic analysis
Kevin J. Downes1,2*, Min Dong2, Tsuyoshi Fukuda2,3, John P. Clancy3,4, Christopher Haffner5, Michael R. Bennett5,
Alexander A. Vinks2,3 and Stuart L. Goldstein3,5

1
Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Division of Clinical Pharmacology,
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 3Department of Pediatrics, University of Cincinnati College of Medicine,
Cincinnati, OH, USA; 4Division of Pulmonology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 5Division of Nephrology

Downloaded from http://jac.oxfordjournals.org/ at EPFL Lausanne on September 8, 2016
and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

*Corresponding author. Present address: Division of Infectious Diseases, The Children’s Hospital of Philadelphia, 3401 Civic Center Boulevard,
Philadelphia, PA 19104, USA. Tel: +1-215-590-4024; Fax: +1-267-426-6629; E-mail: downeskj@email.chop.edu

Received 3 March 2016; returned 27 April 2016; revised 21 July 2016; accepted 26 July 2016

Background: Tobramycin is frequently used for treatment of bronchopneumonia in patients with cystic fibrosis (CF).
Variability in tobramycin clearance (CL) is high in this population with few reliable approaches to guide dosing.
Objectives: We sought to evaluate the pharmacokinetics of once-daily intravenous tobramycin in patients with CF
and test the influence of covariates on tobramycin CL, including serum creatinine (SCr) and urinary biomarkers:
neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP) and kidney injury molecule-1
(KIM-1).
Methods: This was a prospective, observational cohort study of children/young adults with CF receiving once-daily
intravenous tobramycin from October 2012 to May 2014 at Cincinnati Children’s Hospital Medical Center.
Therapeutic drug monitoring data were prospectively obtained. Population pharmacokinetic analyses were
performed using non-linear mixed-effects modelling.
Results: Thirty-seven patients (median age 15.3 years, IQR 12.7–19.5) received 62 tobramycin courses. A one-
compartment model with allometrically scaled weight for tobramycin CL and volume of distribution (V) best
described the data. Urinary NGAL was associated with tobramycin CL (P,0.001), as was urinary RBP (P,0.001).
SCr, estimated glomerular filtration rate and urinary KIM-1 were not significant covariates. The population pharma-
cokinetic parameter estimates were CL¼8.60 L/h/70 kg (relative standard error 4.3%) and V¼31.3 L/70 kg (relative
standard error 4.7%).
Conclusions: We describe urinary biomarkers as predictors of tobramycin CL using a population pharmacokinetic
modelling approach. Our findings suggest that patient weight and urinary NGAL or RBP could be used to individu-
alize tobramycin therapy in patients with CF.

the CF population and allow for adequate drug clearance (CL)
Introduction
prior to readministration.
Intravenous tobramycin is often used in the management of cys- Serum creatinine (SCr) is a suboptimal marker of kidney injury
tic fibrosis (CF) pulmonary exacerbations because of its bacteri- and function in patients with CF, whose muscle mass is often
cidal activity against Gram-negative pathogens.1 From a reduced.4,5 Estimated glomerular filtration rate (eGFR) frequently
pharmacokinetic/pharmacodynamic (PK/PD) standpoint, amino- underestimates renal impairment in patients with CF and the rela-
glycosides demonstrate concentration-dependent killing2 while tionship between SCr-based estimates of renal function and ami-
prolonged and increased drug exposure increase the risk of noglycoside CL in this population is poor.6 Individualized PK
nephrotoxicity.3 Most clinicians utilize once-daily intravenous monitoring can improve efficacy and minimize toxicity of amino-
bolus infusions of tobramycin during treatment of bronchopneu- glycosides,7 – 9 but SCr measurement may add little to guide ami-
monia to combat the more resistant pathogens encountered in noglycoside dosing in patients with CF.

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30 The relationships between tobramycin PK para.31 Urine cre- which are elevated when tubular reabsorption is impaired and atinine (UCr) was measured by modified Jaffe reaction (Dimensionw Xpand utilize the same proximal tubule receptor as tobramycin. 70)0. measurements was 0.25. were eligible if they had a documented diagnosis of CF. (R&D Systems. guardians as appropriate. All injury (AKI). specifically gentamicin. The residual error was described by a combined additive and proportional model. urine biomarker concentrations and urine bio- conducted in accordance with the principles of the Declaration of Helsinki. The first-order conditional estimation with the interaction option a pulmonary exacerbation and received intravenous tobramycin once daily was used to estimate the PK parameters and their variability. were admitted for Ireland). For days on which biomarkers were unavailable (n ¼ 11/197). gender.Downes et al. Dublin. these biomarkers can also provide func. The interindividual variability for the PK parameters was deter- mined with an exponential error model.0. additional levels were obtained with dose adjustments and at the discretion of the medical team. The three-quarter allometric scaling method [(weight/ or if they failed to provide urine samples on ≥70% of inpatient days. USA for RBP). Aliquots were then frozen at following a course of aminoglycoside therapy even though changes 2808C and stored until analysis was performed.17. We hypothesized that RBP and NGAL. respectively. USA). NY. the scaling coefficient for volume of distribution tobramycin course was completed . Siemens Diagnostics. risk stratification and prognostication of acute kidney 10 mg/kg/dose if the patient had not recently received tobramycin. Study population Population PK model We conducted a prospective. mula32 for subjects ≤18 years of age and the Cockcroft–Gault formula33 ical pharmacists. Since tobramycin commercially available assays (AntibodyShop.24 Kidney injury molecule-1 (KIM-1) is a in all patients receiving tobramycin as part of routine patient care at our Downloaded from http://jac. SCr and tobramycin measurements were of cytotoxicity.20 Retinol-binding protein (RBP) completion of the hospital tobramycin course. where SD is the standard devi- ation of the assay in mg/L.19. C represents the measured tobramycin concen- Patients and methods tration and C 2 is the square of C. tural model. USA).18 years of age.18 Urinary excre. missing values were imputed using the last observation from the same patient. eGFR.org/ at EPFL Lausanne on September 8. RBP and population. creatinine in the CCHMC Center for Acute Care Nephrology biomarker meters.0006 . The study protocol was approved by the We assessed the following covariates: age. marker concentrations corrected for UCr (biomarker/UCr). but other residual error Ethics models such as exponential. NGAL and RBP were measured via ELISA using human-specific trations have also not been previously explored.3 mg/L. additive or proportional were also examined. megalin.0341 . Initial for subjects . lean Institutional Review Board at CCHMC (IRB #2012 – 1231). Samples were stored at 48C for up to via megalin in the proximal tubule. Neutrophil gelatinase-associated patients. SCr was measured daily in SCr are not apparent.10 However. height. each equation was also tested separately 2 of 7 . Denmark for is renally eliminated. per standard of care. weight. and urinary biomarker concen.7 days prior to admission. which is a marker subjects’ clinical characteristics. For the struc- for ≥5 days.11 – 15 is reabsorbed by proximal tubule cells16 via the same ization along with standard-of-care labs when drawn within 12 h of a endocytic receptor as aminoglycosides. Salem. Specimens were centrifuged at 3000 g for 15 min and the superna- tubule dysfunction22.26 and urinary levels institution. laboratory. Only urine samples col- is a hepatically synthesized chaperone for vitamin A transport to lected on days when tobramycin measurements were collected were tissues that is freely filtered by the glomerulus and reabsorbed included in analyses (see below). A subset of sub- lipocalin (NGAL). urinary biomarkers could augment current NGAL and ALPCO.2. We performed by the CCHMC clinical laboratory via coupled enzymatic reaction hypothesized that NGAL and RBP will lead to improvement in (Siemens Dimension Vistaw 1500 Chemistry Analyzer) and turbidimetric the population model fit for CL compared with KIM-1 and sought inhibition immunoassay (Dimension Vistaw. tion is increased secondary to nephrotoxic proximal tubule injury Urine specimens were collected once daily from enrolment through causing impaired reabsorption.21 It is a sensitive marker of 72 h. USA) as previously described. Patients mixed-effects modelling with NONMEMw (version 7. are elevated in the setting of both ischaemia and toxin administra- tion. Model selection was based on goodness-of-fit plots with assessment of Informed consent/assent was obtained from patients and their parents/ the objective function value (OFV). eGFR was Dosing regimen and sampling examined using age-appropriate estimating equations: the Schwartz for- Recommendations for dosing of tobramycin were made by inpatient clin. were admitted to the ICU ation were tested. C +0. KIM-1. The lower limit of detection of tobramycin approach. increased in the urine following a variety of kidney jects (n¼32) had tobramycin levels obtained every 3 days during hospital- insults. while KIM-1. Grusbakken.27 – 29 Study procedures Urinary biomarkers have not been studied extensively in the CF Each urine sample was tested for concentrations of NGAL.75] was utilized to account for variability in body weight when esti- Subjects could participate during multiple admissions if their preceding mating tobramycin CL. will not be directly correlated with CL. observational pilot study of children and young adults with CF admitted to Cincinnati Children’s Hospital Medical Center We developed a population PK model for tobramycin using non-linear (CCHMC) over a 20 month period (October 2012 to May 2014). (V) was 1. ICON. 2016 proximal tubule transmembrane protein25. KIM-1 was measured by an individualized PK monitoring strategies to estimate tobramycin ELISA that has been constructed using commercially available reagents renal drug handling. The assay error pattern was described as SD (mg/L) ¼ 0. who were not directly involved with this study. Siemens Diagnostics. MN.24. Minneapolis. will be plus HM Clinical Analyzer.23 and in patients with CF may be increased tants divided into nine 1 mL specimens. Urinary kidney injury biomarkers are clinically useful for early starting doses were based on doses used during previous courses or detection. doses were given as a 30 min infusion. NH. Subjects were excluded if they had received a lung transplant. to assess these relationships using a population PK modelling Tarrytown. one. Serum tobramycin drug concentra- tional information based on the mechanism of excretion and site tions were obtained at 3 and 10 h post-dose on day 1 of therapy in all of interaction within the kidney. NY.oxfordjournals. SCr. Investigators performed all measurements blindly and were unaware of inversely related to tobramycin CL. C 2. Tarrytown.and two-compartment models with first-order elimin- were receiving immunosuppressant medications. This study was body weight.0486 +0. specifically total body CL. preceding dose.

0) NGAL accounting for correlation within subjects and individual admissions. We also tested the effects of other covariates on NGAL includ- concentrations per ing day of therapy. dose (mg/kg and mg). 19%) and linezolid (n¼10. meropenem (n ¼ 18. nor did SCr or eGFR.64) 0. UCr (mg/dL).35 and children. Frequency KIM-1 (pg/mL). RBP (ng/mL). a were described using means (with SD) or medians (with IQR).076). KIM-1/UCr and UCr did not (P .2 (10. b ard errors and an independent covariance structure were used.9 (33. a weighted average correlation coefficient was calculated.1 (23. Covariates that were significantly associated with NGAL values on univari. median (IQR) 73.5– 164. Downloaded from http://jac. median (IQR) 25. College Station. drug doses and drug levels Female gender. Twenty-one (57%) received a single tobramycin course. 12 (32%) received two courses and 4 (11%) received three or more courses.9) 309. for the study population.6 –54. 16%). AUC0 – 24 and biomarkers Weight (kg)b. The one- compartment model with allometric scaling for weight to describe CL and Unique All V (Model 2.41–0.001) from the base model.org/ at EPFL Lausanne on September 8.0– 12.9– 77.2) To examine the relationship between Cmax.2 (19.5– 171.2–73. body weight (kg). Several studies have suggested that a cut-off ate on both V and CL. Inclusion of age and female in adults34. Age (years)b. To account for repeated measurements among subjects.50 (0.38. median.7–530. age (years). The most commonly coadministered antibiotics the PK parameter estimates were within the 95% CIs. We first used validated collinearity between patient weight and NGAL (R 2 ¼ 0.0–144. Covariates were selected using a forward Results addition. RBP and RBP/UCr all sig- cut-off level for AKI (100 ng/mL) and highest NGAL levels reported in our nificantly reduced the OFV (P. 560 (450– 640) 563 (450– 640) Finally.0.40 SCr (mg/dL). we tested the correlation between subject means Height (cm)b. we performed nested linear mixed-effects regression of CL on Initial dose (mg/kg)b. 3 of 7 . Covariates that improved the model fit on univariate analysis by decreasing the OFV by ≥10. median (IQR) two or more concomitant nephrotoxins during the tobramycin course. Summary statistics were ceftazidime (n ¼ 18. There were a total of 307 tobra- Model validation mycin drug concentration measurements over the study period: 103 were drawn between 2 and 4 h post-dose.0 (167. 21%).0 (27.36 Simulations were conducted using the final gender as covariates for CL did not significantly decrease the model with NGAL concentrations that correspond to the lowest.001).01).49 (0. NGAL/UCr.2. remained in the final model. The addition of other covari- simulated AUCs were calculated by the linear log trapezoidal rule. 2016 ate. median (IQR) 318. deterministic simulation was performed based on the time data for our population. which The final study cohort consisted of 37 subjects receiving 62 intra- corresponds to a P value ≤0. Initial dose (mg)b. We next examined the relationships between biomarkers and PK par- ates (biomarkers) to a model including NGAL did not further sig- ameter estimates (CL. median (IQR) 48. The Netherlands)37 to per- form population model-based Bayesian estimation of individual PK par- ameter estimates for each subject each day. clinical PK software (MW/PHARM.8–56. For VPC. The final PK model was evaluated using a non-parametric the study population are shown in Table 1. NGAL provided the tobramycin was given to the patients via 30 min intravenous infusion. ticarcillin/clavulanate (n ¼ 12. to further explore the relationship between daily CL estimates median (IQR) and NGAL.7– 19. 5 samples were below the of simulated concentrations were plotted against the observed data for level of detection.8) ject per tobramycin course and P values computed according to the num. Cmax. not applicable.1–50.0) values. 29%).9) weights were based on the number of repeated measurements per sub. 29%). median (IQR) 15. NA. 167 were drawn Model validation was performed using bootstrap analysis and a prediction- corrected visual predictive check (PC-VPC). The model was considered reliable if (IQR 7 – 13). Derivation of the final population PK model NGAL value of 100 ng/mL has been associated with an increased risk of AKI to describe CL is shown in Table S1.8 (161. height. available as Supplementary data at JAC Online) was Variable subjectsa (N ¼37) admissions (N ¼62) used as the a priori model in the PK software program.3 (12. The demographics and clinical characteristics of comparison.62) Biomarkers were log-transformed due to non-normal distribution of NGAL (ng/mL). median (IQR) 161 (150– 165) 159 (145. At time of tobramycin start. USA). The 5th. fluoroquinolone (n ¼ 13.4) 11. admission number during subject over the entire the study.2–14. weight and gender). Tobramycin serum NA 10 (6–17) ure was CL.0 (10.39 Cmax was determined Table 1. gender. median (IQR) The primary outcome was log-transformed NGAL and the primary expos.0 (40.0.41– 0.5–19. Cmax and AUC0 – 24) via analyses performed using nificantly improve model fit (P . backward elimination process. as appropri. venous tobramycin courses. a ate analysis were combined into a final multivariable model. Robust stand.Biomarkers and tobramycin clearance in cystic fibrosis JAC for all subjects regardless of age. SCr. 50th and 95th percentiles centrations were drawn at other times. 11.0) using Pearson correlation tests accounting for repeated measurements.2) 44.001. 1000 virtual datasets between 9 and 11 h post-dose and the remaining 37 serum con- were simulated using the final model.7 (10. Patient demographics and clinical characteristics as the concentration immediately after the end of the infusion.5) 14. The median duration of tobramycin was 10 days CIs for the population estimates. n (%) 24 (65) 43 (69) were used to generate PK estimates in the software program.3– 530.8) ber of tobramycin courses included in the analysis (n¼60). while study cohort.0.4– 57. TX. median (IQR) 49. median (IQR) 0. Mediware.2) across individuals.0). A typical patient weighing 50 kg was selected and 10 mg/kg KIM-1. aminoglycoside courses in the previous 10 years.3 (26. Weight was an independent covari- final model by NONMEM 7.7 (12.4 (9. Table S1.1 (StataCorp.0) 46. PD relationships PK analysis To assess the relationship between NGAL and tobramycin area under the A one-compartment model best described the concentration – curve (AUC0 – 24).8. All patients were bootstrapping analysis of 1000 samples selected to calculate the 95% Caucasian. There was no Stata 13. NGAL.0) 42. Summary statistics based on first tobramycin course. presence of CF-related diabetes and receipt of study. OFV. Available patient data (age.oxfordjournals.4) 22. The largest reduction in the OFV (219.

4%–24.56 75 Tobramycin AUC0–24 (mg·h/L) Tobramycin AUC0–∞ (mg·h/L) 100 65.4 mg .01). respectively. 309 pg/mL (IQR 161. day of ther- apy.18. concentrations.01).21. As shown.9). 22.0 – 144. RBP/UCr. Minimization and the covariance step were suc. Model 2) on 186 patient days shown in Table S2.21 25 100 412 NGAL level (ng/mL) NGAL level (ng/mL) Figure 1.0). There were no significant differences (IQR 27. 4 of 7 .5% higher NGAL values (95% CI 5. PC-VPC demon.75 77.0.6) and 86.7%.2 ng/mL (IQR 19.5 – 29. cut-off level for AKI and highest NGAL levels reported in our study cohort. (a) Scatterplot of estimated AUC0 – 1 versus measured NGAL for individual subjects (N ¼ 197 measurements).8 – 102.5 – 98. the median. after accounting for repeated measurements dur- centrations. Cmax. 42. P.3 L/70 kg and 8. 604.5 ng/mg (IQR 54. P¼ 0. respectively. h/L (IQR 75. 2016 the final model and were within the bounds of the 95% CIs. which correspond to NGAL levels that are the lowest. Model evaluation Median biomarker values were not significantly different when restricted only to the first tobramycin course for all subjects Goodness-of-fit/diagnostic plots are shown in Figures S1 and S2.8). cessful for the final model. prior aminoglycoside courses and admission number during PD relationships the study were not associated with NGAL. RBP.oxfordjournals.org/ at EPFL Lausanne on September 8. Estimated AUC against urinary NGAL. (b) Estimated tobramycin AUC0 – 24 using the final population PK model in 1000 simulations of NGAL concentrations of 0. Inclusion of urinary NGAL as a (a) (b) 150 100 80. Overall. The final parameter estimates derived from the final model are compartment model (Table S1.Downes et al. There was an inverse cating little bias in the parameter estimates. The mean population parameter estimates obtained ing tobramycin courses.60 L/h/70 kg.7 ng/mL (IQR 10.3 pg/mg (IQR 407. indi.56 74. factors on NGAL are shown in Table S3. strated good agreement between observed and predicted Results of univariate mixed-effects linear regression of clinical concentrations by time after dose (Figure S3).36. P ¼ 0.05).8).60 (all courses) L/h/70 kg. NGAL/UCr.20).35 and the highest reported in our study cohort.071·x + 87 0 0 0 100 200 300 400 0. 103. weighted average PK parameter estimates and biomarker centrations for both the population and individual predicted con.1 – 237. with NGAL concentrations of 0. CL was inversely associated with NGAL after accounting exposure. Simulations were nephrotoxins): a decrease in CL of 1 L/h/70 kg corresponded to conducted to estimate tobramycin AUC0 – 24 using the final model 14.13).1 – 1066.69 (first course only) versus were: NGAL.2 ng/mg 8. The model 26. 25.5). but not Downloaded from http://jac.05 50 50 25 y = 0. we plotted the individual AUC0 – 1 estimations of each for other significant covariates (age and receipt of two or more subject versus NGAL concentrations (Figure 1a). a pulmonary exacerbation. 25. are shown in Table 2. (data not shown).0). On multivariate analyses To further visualize the impact of NGAL on overall tobramycin (Table 3). 100 and 412 ng/mL. 49. KIM-1. There was weak cor- from the bootstrap procedures were similar to the estimates from relation between NGAL and dose (r ¼ 0.25. median. the mean estimates of V and The median Cmax and AUC0 – 24 over all study days were CL were 31. a com- Discussion monly used cut-off level for AKI34. weight-adjusted dose (r ¼20. in NGAL during course 1 versus courses 2 –6 (P ¼0.1 –50. estimates for CL were minimally different when restricted to the respectively. The between-subject correlation of subjects’ There was good agreement between observed and predicted con. 100 and 412 ng/mL.9 mg/L (IQR 23. correlation between tobramycin CL and NGAL (r¼20. Dosage.21. respectively (Figure 1b). and KIM-1/UCr. injury biomarkers and tobramycin PK among a population of chil- PK parameters were estimated using Bayesian estimation with dren and young adults with CF receiving once-daily tobramycin for a validated clinical PK software program and our base one. tobramycin AUC This pilot study explored the relationship between urinary kidney increases with higher urine NGAL levels.5). The median biomarker values over all study days first tobramycin course per subject: 8.3 – 530. P¼0. with both biomarker and tobramycin concentrations available. which correspond to the lowest.

although V was larger. measurements of urinary NGAL in conjunction with Biomarkerb coefficient P value coefficient P value tobramycin levels may allow for improved estimation of an indi- vidual patient’s CL and facilitate AUC-driven dose adjustments. CCHMC in urinary biomarkers among patients with CF has not been stud- pulmonology service patients received intravenous fluids prior to ied. parameters towards the null and should not discredit the relation- tion in patients with CF.08 0. when controlling for reabsorption. Although the effects of aminoglycoside exposure other factors that may influence NGAL.773– 0. A number of population PK models for tobramycin have been Future studies involving patients with a range of underlying kidney developed for children with CF. We did not detect an association between biomarkers col- b Biomarkers log-transformed for comparisons.29 0. RBP and tobramycin calculated as y%¼100×(x21) where x is the coefficient reported above.Biomarkers and tobramycin clearance in cystic fibrosis JAC Table 2.48 tubular dysfunction is the initiating cantly associated with higher NGAL values. this eGFR did not improve our model fit for tobramycin CL. we found that body weight was a signifi. megalin. Therefore.001 We did not find a significant association between tobramycin NGAL/UCr 0.03 0.16 0. We measured urinary biomarkers once daily.0. RBP and CL. Second. cidate the clinical value of urinary biomarkers in the CF population. the not been previously described.19 0. increased biomarkers may reflect change in biomarker (y) per 1 U increase in the covariate can be impaired CL and hence higher AUC.257 (7. 2016 accounting for repeated measurements during 60 tobramycin courses. Future studies will be needed to further elu- a Analyses performed using 186 PK estimates and biomarker pairs. as 5 of 7 . Meanwhile. decreased CL was signifi. First. lected prior to tobramycin start and severity of lung disease as measured by pulmonary function testing (data not shown).45 Measurement of urinary NGAL could supplement traditional Cmax AUC0 – 24 therapeutic drug monitoring practices and provide reassurance that appropriate tobramycin CL is sustained throughout therapy. First. urement was not assessed. Therefore. mycin CL occurring over the course of a day may have affected cant covariate for both CL and V.33 0. regression regression Additionally. Age (years) 1. in particular NGAL. our study was conducted poor predictors of tobramycin CL as well.356– 2.53 to detect changes in renal elimination of tobramycin and avoid development of AKI. Downloaded from http://jac.067 (1. We with CF are often infected with resistant Gram-negative believe that there is biological plausibility to our findings.946) 0.. Although patients RBP/UCr 20. but log-transformed NGAL accounting for correlation within subjects and values were similar when compared among patients with stable admissions disease versus those experiencing a pulmonary exacerbation. serial moni- KIM-1 0. inverse relationship between NGAL and tobramycin CL is rational.oxfordjournals. a However.002 We believe that our findings are also biologically plausible. during tobramycin therapy may result from impaired tubular ment in our population model’s fit. This association has event leading to aminoglycoside nephrotoxicity.26 0. In a study by Zughaier et al. Between-subject correlations of weighted average biomarker organisms and large tobramycin doses may be necessary to concentrations and individual PK parameter estimatesa achieve adequate peak concentrations when the MIC is . However.001 may reflect an exposure – toxicity relationship where increased Intercept 30.619) . the addition times would be needed to estimate PK parameters using a two- of other biomarkers did not further improve the model fit. Most tobramycin concentrations biomarkers.47 Alternatively.4 therefore.881 (1.13 0. NGAL 0.855 (0. The inclusion of urinary as part of routine clinical care. Further. Patients a model of antimicrobial population PK is a novel approach.124) 0. on the kidney are complex. are all substrates for the same endocytic receptor in the proximal tubule.608) .19 0. SCr and would likely bias the association between biomarkers and PK creatinine-based equations do not reliably estimate kidney func.1. it is not surprising that they are ship between NGAL.014– 1. the biological variability to increased total body water: concurrent to the study.19 0.14 0.009 dose and NGAL.org/ at EPFL Lausanne on September 8. compartment model.57 0. did lead to an improved model for fell in two time periods: 2 – 4 or 9 – 11 h.15 0. no patients had a doubling of their creatinine (data not Biomarkers were log-transformed for regression and coefficients reported shown).80 in our study had stable tobramycin CL over therapy. Additional sampling tobramycin CL.02 20. findings.0. determination of normal serum and urinary NGAL Variablea Estimatea (95% CI) P value values in patients with CF is necessary to promote its clinical usefulness. inclusion of urinary biomarkers into Our findings may have important clinical implications. NGAL.15 0. inclusion of SCr and the relationship between the biomarkers and CL. The larger V may have been secondary There are limitations to our study.46 . Multivariable linear mixed-effects model of covariates on higher in patients with CF compared with healthy controls. After NGAL was included in the model.01 the positive association between NGAL and tobramycin AUC0 – 24 Receipt of ≥2 concomitant nephrotoxins 1. but the timing the initiation of tobramycin until their urine specific gravity was between tobramycin administration and urinary biomarker meas- .590– 120.0.32 toring of urinary biomarkers can provide a non-invasive means KIM-1/UCr 0. CL (L/h/70 kg) 0. suggesting possible subclinical injury detected best by have been exponentiated (10x) for display in this table. The percentage urinary NGAL. Lastly.1 mg/ L.46 serum NGAL concentrations were Table 3.07 0.41 – 44 The population estimate for function may further elucidate the mechanism underlying our CL in our study was similar to previously described models.001 AUC0 – 24 resulting from large doses leads to direct tubular injury.010 as part of a quality improvement project to reduce AKI.25 and NGAL may be driven by CL (AUC ¼dose/CL). suggesting that the relationship between AUC RBP 20. and increased excretion of urinary NGAL and RBP covariate on tobramycin CL led to the most significant improve.15 0. Fluctuations in biomarkers or tobra- As with previous models.

Vancouver. Crit Care Med 2008. 2908. 9: 124– 9. San Diego. Strong RK et al. Greville H. J Am Soc Nephrol 2 Mouton JW. J. of serum and urinary biomarkers may provide further evidence 4 Al-Aloul M. S. Vyskocil AA. Serum neutrophil gelatinase- ported in part by the Agency for Healthcare Research and Quality Center associated lipocalin (NGAL) as a marker of acute kidney injury in critically for Education and Research on Therapeutics grant (AHRQ CERT ill children with septic shock. C. Pediatric Academic Societies on clinical outcome: a cost-effectiveness analysis. Lancet 2005. D. D. in a population model for tobramycin CL 6 Alghanem S. most specifically NGAL. Comparison of the course of bio- References marker changes and kidney injury in a rat model of drug-induced acute 1 Flume PA. studies are needed that further explore dosed by using individualized pharmacokinetic monitoring. Franck PA et al. J Clin Invest 1995. Am J Respir Crit Care 21 Christensen EI. 96: Supplementary data 1404– 13. 15 Wheeler DS. receives grant support from the National Heart. J Infect Dis and validate the PK/PD relationship described here.Downes et al. PA. 167: 173–9. Mahieu P et al. 12 Gaspari F. The study was also supported by a CCHMC Cystic Fibrosis Research and 14 Hirsch R. The endocytic receptor megalin Transparency declarations binds the iron transporting neutrophil-gelatinase-associated lipocalin with None to declare. Canada. National Institute of Child Health and Human Development of the National 13 Mishra J. investigation 1993. detection of kidney injury. Cystic fibrosis pulmonary kidney injury. Clin Chem risk factors for aminoglycoside-associated nephrotoxicity in patients 1987. AMIN09YO). Bell G et al. Philadelphia. 180: 802–8. gelatinase-associated lipocalin levels reflect damage to glomeruli. Mukoyama M et al. 6 of 7 . Robinson KA et al. Acknowledgements 9 van Lent-Evers NA. 20 Sasaki D. 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Neutrophil gelatinase-associated lipocalin: Ma for performance of urinary biomarker measurements. high affinity and mediates its cellular uptake. K. Lung. Pediatr Nephrol 2007. Pfriem H et al. Vorum H et al. Lee HT. Urinary neutrophil at JAC Online (http://jac. 23: 194–200. Diagn Microbiol Infect Dis 2005. Mori K. 2016 icity and fewer associated costs. Pharmacodynamics of tobramycin 1999. Ther Drug Monit Meeting (abstract no. Yamada A. FEBS Lett 2005. 46). 55: 2528– 31. Training Program in Pediatric Clinical and Developmental Pharmacology. Mori K. 16: 553–66. Future studies are needed to validate and further explore 7 Drusano GL. Dent C. 17 Hvidberg V. Touw DJ et al. kers of creatinine and eGFR among children and young adults J Antimicrob Chemother 2013. Devarajan P. Mogayzel PJ Jr. However. 579: 773–7. IDWeek 2014 (abstract no. 365: 1231– 8. was supported by a Thrasher Research Fund Early Career Award tion: a pilot prospective case – control study. 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Optimization of aminoglycoside therapy. 115: 610– 21. Coulthard K et al. 1U19HS021114). 33: 775–9. Evidence for an essential Med 2009. Impact of goal-oriented Portions of this work were presented as abstracts at CRRT 2014 (abstract and model-based clinical pharmacokinetic dosing of aminoglycosides no. What is the best method relating to functional processes at sites within the kidney. NP and Jeanne Weiland. 399). Geus WP et al. is sup. Nephron Clin Pract (Thrasher Award number 9189). We for measuring renal function in adults and children with cystic fibrosis? describe for the first time that inclusion of urinary biomarkers. NGAL is an early predictive biomarker of Development Program Pilot & Feasibility program grant (to K. Moskaug JO. G. Institute of the National Institutes of Health (NHLBI-FOA-HL 12 – 035) and the Cystic Fibrosis Foundation (R457-CR11. Ma Q et al. Vorum H et al.org/). with subject recruitment and coordination of study procedures and Qing 11 Mishra J. 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