AAC Accepted Manuscript Posted Online 22 May 2017

Antimicrob. Agents Chemother. doi:10.1128/AAC.00205-17

Copyright 2017 American Society for Microbiology. All Rights Reserved.

1 A population pharmacokinetic model of gentamicin in paediatric oncology

2 patients to facilitate personalised dosing
3 Llanos-Paez CC1#, Staatz CE1, Lawson R2, Hennig S1
4 1. School of Pharmacy, The University of Queensland, Brisbane QLD, Australia
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2. The Lady Cilento Childrens Hospital, Brisbane QLD, Australia
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9 Running title: Gentamicin PK model in paediatric oncology patients
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17 Manuscript word count: 4329
18 Abstract word count: 235
19 Number of tables: 3
20 Number of figures: 2
21 Number of references: 45
22 Supplemental material: 1 Figure & 1 Table
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24 #Corresponding author: Ms Carolina Consuelo Llanos Paez, Pharmacy Australia Centre of
25 Excellence (PACE), The University of Queensland, 20 Cornwall Street, Woolloongabba,
26 Queensland, Australia 4102, email: c.llanospaez@uq.edu.au.
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28 Keywords: pharmacokinetics, gentamicin, NONMEM, paediatrics, oncology
29

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30 ABSTRACT

31 To ensure safe and effective dosing of gentamicin in children therapeutic drug monitoring

32 (TDM) is recommended. TDM utilising Bayesian forecasting software is recommended, but

33 is unavailable as no population model exists that describes the pharmacokinetics of

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34 gentamicin in paediatric oncology patients. This study aimed to develop and externally

35 evaluate a population pharmacokinetic model of gentamicin to support personalised dosing in

36 paediatric oncology patients. A non-linear mixed effect population pharmacokinetic model

37 was developed from retrospective data. Data were collected from 423 patients for model

38 building and a further 52 patients for external evaluation. A two-compartment model with

39 first-order elimination, best described gentamicin disposition. The final model included renal

40 function (described by fat-free mass and post-menstrual age) and serum creatinine as

41 covariates influencing gentamicin clearance (CL). Final parameter estimates were as follow

42 CL: 5.77 L/h/70 kg; central volume of distribution: 21.6 L/70 kg, peripheral volume of

43 distribution: 13.8 L/70 kg and intercompartmental clearance: 0.62 L/h/70kg. External

44 evaluation suggested that current models developed in other paediatrics cohorts may not be

45 suitable to use in paediatric oncology patients, as they showed a tendency to over-predict

46 observations in this population. The final model developed in this study displayed good

47 predictive performance during external evaluation (root mean squared error: 46.0% and mean

48 relative prediction error: -3.40 %) and may therefore be useful to personalise gentamicin

49 dosing in this cohort. Further investigations should focus on evaluating the clinical

50 application of this model.

51

2
52 INTRODUCTION

53 Febrile neutropenia induced by chemotherapy is a common complication in paediatric

54 oncology patients. Neutropenic patients are more susceptible to developing infections (1).

55 Sepsis is the primary cause of mortality and morbidity in oncology children with febrile

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56 neutropenia (2). Mortality due to sepsis is 1.6 fold higher for oncology paediatric patients

57 than it is for other paediatrics (3). Aminoglycoside antibiotics such as gentamicin, in

58 combination with other broad-spectrum antibacterial agents, play an important role in

59 managing infectious complications in these individuals and are used as second line therapies

60 when treating Gram-negative infections and when resistance develops to first line agents (4).

61 Gentamicin has a narrow therapeutic window and displays large pharmacokinetic

62 variability. High and prolonged exposure to gentamicin has been associated with nephro- and

63 ototoxicity (5, 6). Paediatric oncology patients often receive long courses of gentamicin on

64 multiple occasions alongside chemotherapy, which further increases the risk of toxicity.

65 Physiological changes (e.g. presence of fever, augmented renal clearance, decreased

66 muscle mass or malnutrition) in oncology patients and administration of chemotherapy can

67 alter patients body composition and the pharmacokinetics of gentamicin, increasing the

68 difficulty of identifying the optimal dose (7-9). Increased clearance (CL) and volume of

69 distribution (Vd) for gentamicin has been seen in adults (7) and paediatrics with cancer (8,

70 10). Augmented renal clearance, possibly due to systemic inflammation, also has been

71 reported in febrile neutropenic patients (11). However, when CL of gentamicin was

72 normalized by body surface area, it decreased in those patients receiving prior nephrotoxic

73 chemotherapy compared to those who did not receive nephrotoxic chemotherapy (8).

74 The Australian Therapeutic Guidelines (12) recommend that for safety and efficacy

75 reasons, aminoglycoside antibiotic doses should be adjusted based on a computerised method

76 such as Bayesian forecasting. While the log-linear regression method is more commonly used

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 77 (13) it may be more invasive, tedious and reactive in nature compared to Bayesian

78 forecasting. The former requires at least 2 blood sample measurements for predictions (14)

79 in contrast to Bayesian forecasting, which may require only 1 sample; and it is not able to

80 give dosage predictions until a dose has first been administered. In adults with febrile

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81 neutropenia, a Bayesian approach has been shown to increase the number of patients

82 achieving desired target exposure to gentamicin compared to using the log-linear regression

83 method (15).

84 To be able to perform dosage individualisation through Bayesian forecasting a

85 population pharmacokinetic model, first needs to be developed which characterises typical

86 pharmacokinetic parameter values, between- and within-subject pharmacokinetic variability

87 and influential covariate factors associated with the drug of interest in the cohort receiving

88 such therapy. Few population pharmacokinetic models of gentamicin have been developed in

89 children between 2 and 18 years of age (16-18), and to our knowledge no models currently

90 exist specifically characterising paediatric oncology patients. Application of a relevant

91 population model in a Bayesian forecasting program would likely improve dosing

92 individualisation of gentamicin in paediatric oncology patients (15, 19).

93 This study aimed to describe the population pharmacokinetics of gentamicin in paediatric

94 oncology patients with febrile neutropenia; evaluate covariates influences, such as

95 concomitant chemotherapy treatment; characterise pharmacokinetic variability in this

96 population and externally evaluate the predictive performance of this model as well as

97 previously published models in a separate patient cohort.

98 METHODS

99 Patients and Data

100 Data for model building and model evaluation were collected retrospectively from the

101 medical records of paediatric oncology patients at the Lady Cilento Childrens Hospital,

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102 Brisbane, Australia (formally known as the Royal Childrens Hospital). These patients

103 received gentamicin and had drug concentrations measured during routine therapeutic drug

104 monitoring (TDM) between 2008 and 2013 (model-building data set) and 2014 and 2015

105 (model-evaluation data set). Ethics approval for this study was obtained from the University

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106 of Queensland Human Research Ethics Unit (approval number: 2012001308) and the

107 Childrens Health Queensland Hospital and Health Service Human Research Ethics

108 Committee (approval number: HREC/12/QRCH/162).

109 Information on gentamicin dosing regimens, timing of dose administration,

110 gentamicin serum drug concentrations and time of sample collection for drug measurement

111 along with patient age, sex, total body weight, height, serum creatinine concentration (Scr)

112 and body temperature readings were recorded. In addition, information on the date,

113 administration time and dose of specific nephrotoxic drugs (cisplatin and carboplatin)

114 patients received within 6 months preceding gentamicin usage were collected.

115 Gentamicin treatment and blood sampling

116 Paediatric oncology patients with a neutrophil count <1.0 cells/mm3 who developed a

117 fever (temperature 38.5 C for at least 1 hour or 38.0 C for at least 2 hours) and who were

118 considered critically ill or at high risk received gentamicin in addition to empiric broad

119 spectrum penicillin based therapy. Gentamicin was also added as directed treatment if Gram-

120 negative positive cultures were confirmed. Gentamicin was given as a 30 minute infusion

121 once daily, initiated at a dose of 7.5 mg/kg for patients under 10 years of age and 6 mg/kg for

122 patients over 10 years according to local hospital guidelines. Blood samples for measurement

123 of gentamicin serum concentrations during TDM were generally taken at 2 hours and 6-12

124 hours post-infusion. In addition, based on clinical judgment, samples before a subsequent

125 dose (trough levels) were sometimes taken.

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126 Gentamicin Assay

127 Gentamicin drug concentration in serum was measured using a fluorescence

128 polarization immunoassay method at the Pathology Queensland Central laboratory, Brisbane,

129 Australia. Different immunoassays were applied over time. From 2008 to August 2011, a

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130 Beckman Coulter PETINIA Immunoassay run on a Beckman Coulter DXC800 Analyser was

131 used. From August 2011 to November 2011, an Abbott CMIA Immunoassay run on the

132 Abbot Architect i1000 Immunoassay Analyser was used. From November 2011 to December

133 2012, a Beckman Coulter CEDIA Immunoassay run on a Beckman Coulter DXC800

134 Analyser was used. From December 2012 onwards a Beckman Coulter PETINIA

135 Immunoassay run on a Beckman Coulter DXC800 Analyser was used. Assay lower limit of

136 quantification (LLOQ) varied across immunoassay method from 0.3 to 0.6 mg/L. Within- and

137 between-assay coefficients of variation were below 10% for all immunoassays employed.

138 Population Pharmacokinetic Analysis

139 Software

140 Population modelling was performed using NONMEM software v.7.3 (Icon

141 Development Solutions, Ellicott City, MD, USA) (20) with an Intel FORTRAN compiler

142 and PsN (Perl-speaks-NONMEM) version 3.5.3 (21). Typical population pharmacokinetic

143 parameters of gentamicin as well as between-subject (BSV) and between-occasion variability

144 (BOV) and residual unexplained variability (RUV) were estimated via the first-order

145 conditional estimation method with interaction (FOCE+I). Xpose (version 4.4.0;

146 http://xpose.sourceforge.net) and R studio software version 3.1 (http://www.r-project.org./)

147 were used for data exploration and visualization.

148 Model development

149 Firstly, a base model was developed by testing one-, two- and three- compartment

150 structural disposition models with first-order elimination. Pharmacokinetic parameter values

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151 were assumed to be log-normally distributed. BSV was modelled using an exponential model

152 (equation 1), and initially applied to all pharmacokinetic parameters and removed if not

153 supported. BOV was modelled using an additional random effects parameter (equation 2) and

154 tested one by one on CL and Vd.

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155 P = TVP e , (1)

156 P = TVP e( , , )
(2)

157 Here, TVP is the typical population parameter estimate and is the parameter estimate for

158 individual i, i,P is a symmetrically distributed random variable with a mean of zero and

159 variance of 2BSV_P, where the square root of the variance represents the reported BSV, and

160 is the parameter value for individual i on the jth occasion, ki,P is the within patient random

161 effect, which is independent and normally distributed with a mean of zero and variance of

162 2BOV_P. Proportional, additive and combined models and different error models for

163 concentration measured using different assays were compared during model building to

164 describe RUV. Gentamicin drug concentrations reported as below LLOQ were substituted

165 with LLOQ/2 values (22).

166 Clinical factors investigated for an influence on the pharmacokinetics of gentamicin

167 included patients renal function (described by body size and age), Scr measurements, sex,

168 use of nephrotoxic drugs and body temperature. After a structural base model was

169 established, potential covariates were screened initially via graphical exploration, considering

170 shrinkage (23). Covariate model building was in the first instant based on physiological

171 plausible covariate parameterization informed by principles of allometric scaling, maturation

172 of glomerular filtration rate, and standardization for age-expected serum creatinine

173 concentration.

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174 The impact of changes in renal function due to maturation on gentamicin clearance

175 was included using the glomerular filtration rate prediction model developed by Rhodin et al.

176 (GFRmat; mL/min, see equation 3) (24). Three descriptors of body size were tested in the

177 GFRmat equation: total body weight, normal fat mass (NFM) (25) and fat-free mass (FFM)

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178 (26). Both, FFM and fraction of fat mass were used within the NFM calculation with the

179 fraction of fat mass being estimated. Allometric scaling (27, 28) using each of these three

180 descriptors of body size (total body weight, NFM and FFM) was applied to all other

181 clearance and distribution parameters according to equation 4.

( ) . ( ) .
182 GFR = . 112 (3)
. ( ) .

( )
183 P = TVP (4)

184 Here, P is the parameter of interest, TVP is the typical population parameter value, the

185 size descriptori represents either body weight, FFM or NFM (kg) for an individual i, which

186 was standardised to 70 kg, to ease comparison to adult values. PMA is post-menstrual age

187 (weeks), calculated for each child by addition of 40 weeks, presenting a typical gestation

188 period, to their post-natal age.

189 Afterwards, Scr and body temperature were subsequently tested using a linear,

190 exponential and/or power model. An inverse relationship between Scr and CL was examined,

191 with Scr standardised to the mean expected creatinine concentration for a person of the

192 relevant age and sex (29). For patients who had a Scr measurement below the lowest

193 reportable limit (< 30 mol/L), this value was fixed to the mean expected physiological

194 creatinine concentration for a person of the relevant age and sex (29). The categorical

195 covariates, sex and use of cisplatin and/or carboplatin within 6 months prior to the gentamicin

196 observation, were tested by estimating the typical parameter value for the most common

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197 category and then obtaining the fractional difference in the parameter value for the second

198 category, compared to the first category.

199 Model selection and internal model evaluation

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200 For nested models, the difference between a pair of objective function values (OFV)

201 for two models approximates the Chi-square (X2) statistic which can be tested for

202 significance (X21, 0.05 = 3.84). The Akaikes information criterion (AIC) was used for non-

203 nested models. Further support for model selection was obtained by evaluating the difference

204 in the magnitude of the change in explained parameter variability (EPV) after covariate

205 inclusion compared to the base model (30). Basic goodness-of-fit plots for observations

206 versus population predictions and conditional weighted residuals versus time after dose were

207 examined for internal model evaluation. Model predictive performance was assessed by

208 generating visual predictive check (VPCs) plots based on 500 simulations. Plot of normalized

209 prediction distribution errors (npde) versus time after dose based on 1000 simulations were

210 also generated and evaluated. Precision of model parameters was obtained from the relative

211 standard errors and confirmed through non-parametric bootstrapping of the final model with

212 1000 replicates.

213 External model evaluation of the final model and models published in the literature

214 The model-evaluation data set was used to externally evaluate the predictive

215 performance of the final model as well as any previous population models of gentamicin

216 published in the literature that were based on paediatric patients. A literature search was

217 conducted in September 2016 using PubMed and EMBASE databases with a restriction on

218 English language publications to identify previously published population pharmacokinetic

219 models. The following keywords were used during the search: gentamicin, paediatric,

220 pharmacokinetics, population pharmacokinetics. Models were included if they were

221 developed in a paediatric population with a post-natal age 5 months using a compartmental

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222 approach and were excluded if they did not provide enough information to be fully

223 reproducible.

224 Each selected population pharmacokinetic model was implemented using

225 NONMEM software, as stated above. Gentamicin concentrations were predicted using

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226 information on the gentamicin dosing regimen, time of sample collection for drug

227 measurement and relevant patient covariate values recorded for the evaluation data set, with

228 pharmacokinetic parameter values and covariate relationships set as determined in the final

229 model and in the previous publications. The predictive performance of each selected

230 population pharmacokinetic model was assessed visually (predicted concentration (Cpred) vs.

231 observed concentration (Cobs) plots and VPC plots) and numerically. Bias and precision were

232 calculated using the relative root mean square error (RMSE %) (equation 5) and mean

233 relative prediction error (MRPE %) (equation 6) (31):

234 RMSE (%) = 100 (5)

235 MRPE (%) = 100 (6)

236 RESULTS

237 Patients and Data

238 Data from a total of 423 paediatric oncology patients (219 males (52%)) with 2422

239 gentamicin concentration-time data points were used for model development. 88% of these

240 patients had febrile neutropenia and 12% had fever-free neutropenia. Patients median (range)

241 post-natal age was 5.2 years (0.2 18.2 years), weight was 19.4 kg (4.8 102.8 kg) and FFM

242 was 15.7 kg (3.4 72.6 kg), respectively. Seventy-three patients (17%) were younger than 2

243 years, 247 patients (59%) were 2 to 10 years old and 103 patients (24%) were older than 10

244 years. Gentamicin concentration measurements ranged from 0.3 to 62.5 mg/L with sampling

245 times after the end of the infusion ranging from 0.5 to 36.0 hours. A total of 372 (15%) of

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246 gentamicin measurements were below the LLOQ at an average of 15 hours after dose. For

247 model evaluation, data from 52 paediatric oncology patients (22 males (42%)) with 174

248 gentamicin concentration-time points were used. Patients median (range) post-natal age was

249 7.9 years (0.7 16.8 years), weight was 22.2 kg (6.2 121.0 kg) and FFM was 20.5 kg (5.3

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250 62.2 kg), respectively. Eight patients (15%) were younger than 2 years, 33 patients (63%)

251 were 2 to 10 years old and 11 patients (21%) were older than 10 years. Gentamicin

252 concentration measurements ranged from 0.5 to 30.8 mg/L with samples taken from 0.75 to

253 34.3 hours after the end of the infusion. A total of 16 (9%) gentamicin measurements were

254 below the LLOQ. Key patient demographic characteristics, laboratory values and gentamicin

255 dosing information are summarised in Table 1.

256 Pharmacokinetic model

257 A two-compartmental model with first-order elimination best described the data

258 (OFV=-332.7 compared to a one-compartmental model). Typical CL estimated was 5.77

259 L/h/70 kg and typical central volume of distribution (V1) was 17.4 L/70 kg. BSV was

260 estimated for CL, V1 and peripheral volume of distribution (V2), including a correlation

261 between CL and V1 (OFV= -156.5) and BOV on CL (OFV= -516.4).

262 Inclusion of GFRmat on CL and either FFM, body weight or NFM on V1,

263 intercompartmental clearance (Q) and V2 improved the fit and increased explained

264 variability. Using any body size descriptor (body weight, NFM or FFM) in the GFRmat

265 equation and for V1, Q and V2 resulted in a significant drop in the OFV (OFV=-406.6,

266 OFV=-403.1 and OFV=-408.3, respectively) (Supplemental material Table S1). However,

267 according to the AIC, FFM fit the data best compared to body weight and NFM. Addition of

268 GFRmat increased EPV on CL (EPV=1.15 L/h), as did inclusion of FFM on V1

269 (EPV=12.67 (L)) (Supplemental material Table S1). In addition to GFRmat, inclusion of an

270 association between Scr measurement and gentamicin CL using a power model (OFV=-

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271 324.2) further significantly improved the fit. Inclusion of Scr increased EPV on CL compared

272 to the previous model that included only GFRmat (Supplemental material Table S1). In

273 subsequent steps, inclusion of use of nephrotoxic drugs and body temperature on gentamicin

274 CL resulted in non-significant improvements (OFV=-2.80 and -1.30, respectively). Typical

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275 pharmacokinetic parameter estimates for the base and final model are shown in Table 2.

276 Model selection and internal model evaluation

277 VPC plots associated with the final model indicated good agreement between the

278 observed and predicted data (Figure 1). VPC, npde and goodness of fit plots associated with

279 the final model are shown in Figure 1.

280 Results from the non-parametric bootstrap were in agreement with the population

281 pharmacokinetic parameters in the final model with narrow 95% confidence intervals (see

282 Table 2). As eta-shrinkage on CL, V1 and V2 was relatively high in the final model (43%,

283 58% and 66%, respectively), diagnostic use of goodness-of-fit plots was limited (23) and

284 these have not been presented.

285 External model evaluation of the final model and models published in the literature

286 From the literature search only three population pharmacokinetic models of

287 gentamicin developed in paediatric populations were identified (Table 3) (16, 17, 32). These

288 models together with the final model from this study were tested regarding their predictive

289 performance with the external dataset. Observed versus population predicted concentration-

290 time plots and VPC plots obtained from all four models generated during external evaluation

291 are displayed in Supplemental material Figure S1 and Figure 2 respectively. Of the four

292 models evaluated the final population model developed in this study was the least biased with

293 a MRPE (%) of -3.40 and the most precise with a RMSE (%) of 46.0 compared to the other

294 models tested (Figure 2).

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295 DISCUSSION

296 This study developed and externally evaluated a population pharmacokinetic model of

297 gentamicin in paediatric oncology patients that could be used to improve dosage adjustment

298 of this drug in this cohort in the future. The final model included an effect of renal function

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299 on CL and FFM on all pharmacokinetic parameters. Prior use of nephrotoxic agents, cisplatin

300 and carboplatin, was not identified as having a significant influence on the CL of gentamicin,

301 after taking into consideration maturation changes in renal function and potential function

302 impairment observed given patients Scr concentration. FFM was identified as the best

303 descriptor to model the influence of body size on gentamicin CL, V1, Q and V2. The final

304 model displayed good predictive performance, when applied to a new dataset not used for

305 model development.

306 Selection of a two-compartment model with first order elimination to describe the

307 disposition of gentamicin in this study is in agreement with a number of studies performed in

308 non-oncology children, neonates and adults included in a recent review (33). Only one

309 population pharmacokinetic model of gentamicin has been developed previously in children

310 who were of a similar age to those included in this study (18). This previous study involved

311 non-oncology children (median age of 2.4 years) who received gentamicin intramuscularly

312 (18). Typical gentamicin apparent CL (CL/F) in these children (7.21 L/h/70kg for a patient

313 with an average Scr of 33.0 mol/L), was higher than that estimated in this study based on

314 intravenous administration (5.77 L/h/70kg for a patient with an average Scr of 37.4 mol/L).

315 Two studies have been performed in paediatric oncology patients, but using non-

316 compartmental analysis methods (8, 10). In the first study (8), typical CL of 9.33 L/h/70kg

317 and 10.3 L/h/70kg was reported in paediatric patients receiving and not receiving

318 chemotherapy, respectively. In the second study (10), typical CL of 8.10 L/h/70kg was

319 reported. Comparison of CL of gentamicin obtained in this study with values published in the

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320 literature is difficult because most previous studies are primarily based on neonates or infants

321 and involved different analysis techniques. Typical V1 estimated in this study (21.6 L/70kg)

322 was similar to other reports, however lower than that reported previously in non-oncology

323 children (24.5 L/70kg) and pre-term neonates (31.1 L/70kg) and higher than that reported in

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324 term neonates (19.3 L/70kg) (33).

325 The final model included an effect of body size in terms of FFM on all

326 pharmacokinetic parameters. When the final model was applied in an external dataset, it

327 predicted gentamicin concentrations more accurately and precisely than a model using NFM

328 on all pharmacokinetic parameters. A recent review on population pharmacokinetic models of

329 gentamicin found total body weight was the most common covariate included as a body size

330 descriptor on CL and V1 (33). Considering that before 2015 no FFM equation for paediatrics

331 was available (26) the inclusion of FFM in models for paediatric populations was limited.

332 This study found FFM explained more variability between subjects than other body size

333 descriptors, possibly due to the fact that gentamicin is highly hydrophilic and mainly

334 distributes into muscle mass or lean body weight rather than fat. One study of gentamicin in

335 elderly patients has included FFM on V1 (34) and another has reported that FFM improved

336 prediction of GFR in paediatric patients (24).

337 An equation describing changes in renal function over time due to organ maturation

338 (GFRmat) was utilised here. This equation was originally developed from a large study

339 involving 923 patients, from premature neonates to young adults, of which most had normal

340 renal function and only 5% were known oncology patients (24). We found that additional

341 inclusion of Scr on CL after consideration of renal function maturation through GFRmat

342 improved model fit further. An accurate bedside estimate of renal function does not exist for

343 young children and Scr is not generally considered to be a good marker to describe renal

344 function maturation in paediatrics, especially in oncology patients due to the lack of muscle

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345 mass (35). Though, in this study, for patients with a Scr > 30 mol/L, Scr appears to be a

346 marker of renal dysfunction, which is not being accounted for in the GFR renal maturation

347 equation. According to our final model a two-fold increase in Scr in patients with Scr levels >

348 30 mol/L led to a 32% decrease in gentamicin CL. Inclusion of Scr in the model was

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349 supported further by an increase in EPV and significant drop in OFV. A limitation of using

350 Scr in this study was that 52% of Scr measurements were < 30 mol/L; thus the model does

351 not account for renal dysfunction in patients with a Scr < 30 mol/L. Inclusion of covariates

352 resulted in a large decrease in BSV in CL and V1 between the base and the final model,

353 namely 28% and 29%, respectively (Table 2). Both BSV and BOV were below 20% for CL,

354 however BOV was slighter higher than BSV which may be due to underlying changes in the

355 patients physiological condition with cancer treatment over time.

356 Usage of cisplatin and carboplatin, was not found to have a significant effect on

357 gentamicin CL. It should be noted however that only 24% of patients received these drugs in

358 the 6 month period prior to gentamicin administration, the window considered during

359 modelling. This window may be too wide or narrow for examination (36, 37) and cumulative

360 lifetime use was not assessed. Moreover, inclusion of patient Scr values within the model

361 may already account for any potential nephrotoxicity caused by these agents. Further

362 attempts were made to assess the influence of cumulative doses of cisplatin and carboplatin

363 and the timing of their co-administration on gentamicin CL, but no significant relationships

364 were identified.

365 One previous study reported that body temperature can influence gentamicin CL in

366 paediatric patients (18). Here, the influence of body temperature on gentamicin CL did not

367 show significance. Body temperature may not have been a suitable marker for critically ill

368 patients here, possible due to the potential use of antipyretics, resulting in a median body

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369 temperature of 36.6 C during gentamicin therapy. Information on antipyretic usage was not

370 collected in this study, however is part of the standard treatment for febrile neutropenia.

371 Previous pharmacokinetic studies using non-compartmental pharmacokinetic analysis

372 suggested gentamicin starting doses between 7.5 and 10.8 mg/kg for paediatric oncology

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373 patients (8, 10, 38). While exposure targets have not been fully elucidated in this population,

374 guidelines typically recommend an area under the concentration-time curve (AUC24) to

375 bacteria minimum inhibitory concentration (MIC) ratio (AUC24/MIC) between 80 to 100

376 and/or a maximum concentration (Cmax) to MIC (Cmax//MIC) ratio greater than 10 to be

377 targeted (39, 40). These targets are obtained from clinical studies performed in adults and

378 consider several different microorganisms (41, 42). Given these targets and the estimated

379 population CL in this study an initial dose of 8.0 mg/kg would be required for a typical

380 patient in this study to achieve this target, which is in agreement with previous dose

381 recommendations in this population.

382 External model evaluation showed that previously published paediatric models over-

383 predicted exposure compared to our model. This is not unexpected, as previous models, even

384 though only models including paediatric patients were considered, were based on different

385 patient cohorts in terms of age, disease state and medication usage. In addition, two out of

386 three previous models evaluated in this study (16, 32) did not scale CL using an allometric

387 weight with an exponent of 0.75. This may partly explain the poor performance of these

388 models in predicting gentamicin concentrations in our paediatric oncology patients (28). This

389 reinforces that a population pharmacokinetic model should not be applied too far beyond the

390 cohort characteristics in which it was developed.

391 Based on a visual and numerical assessment the final model presented in this study

392 displayed good predictive performance and should be clinically useful in the paediatric

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393 oncology setting. In addition, all PK parameters were estimated with relative standard errors

394 (RSE%) below 20%.

395 This study had limitations in terms of the sparse number of samples per patient per

396 dose collected from TDM data available. This is common in special population such as

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397 paediatrics (43) and may have led to the higher eta-shrinkage and limited the use of

398 diagnostic plots of individual parameter estimates and covariates (23). Furthermore, this

399 study involved retrospective data collection, which relies on the accuracy of written medical

400 charts.

401 After implementation of the model in a Bayesian forecasting program, future studies

402 should focus on evaluating its clinical applicability to personalise gentamicin dosing

403 regimens, ability to reduce blood sampling during TDM and capacity to improve target

404 attainment compared to current practice in paediatric oncology patients (10).

405 CONCLUSIONS

406 To the best of our knowledge this study presents the first population pharmacokinetic

407 model for gentamicin in paediatric oncology patients with febrile neutropenia. This model

408 was developed based on physiological plausible covariate parameterization informed by

409 principles of allometric scaling, maturation of glomerular filtration rate, and standardization

410 for age-expected serum creatinine concentration. Serum creatinine measurement in this

411 model accounted for renal dysfunction not explained by maturation. The model developed

412 displayed superior predictive performance compared to a very limited number of models

413 currently describing gentamicin pharmacokinetics in paediatric patients. This model is now

414 available to be implemented in a Bayesian forecasting program such as TDMx

415 [http://www.tdmx.eu/] (44) for initial dose individualisation and adaptive dose adjustment of

416 gentamicin in paediatric oncology patients, to improve achievement of individualised

417 exposure targets.

17
418 ACKNOWLEDGEMENTS

419 The authors would like to acknowledge the Australian Centre of Pharmacometrics for

420 the hardware and NONMEM software licences. CCLP was supported by Becas Chile

421 (CONICYT) through a scholarship and the University of Queensland Graduate School

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422 International Travel Award.

423 No external funding supported this study.

424 AUTHORS CONTRIBUTION

425 CCLP collected and analysed the data and wrote the manuscript. CES, RL and SH applied

426 for the ethical approval, supported data collection and critical review of the manuscript. CES

427 and SH supported and reviewed the data analysis and contributed to the writing of the

428 manuscript.

429

18
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555

556
557

24
558 FIGURE LEGENDS

559
560 FIG 1 (a) Visual predictive check plot based on 500 simulations associated with final

561 population pharmacokinetic model. Observed data (grey dots), median, 95th and 5th

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562 percentiles of observed data (red line), median, 95th and 5th percentiles of simulated data

563 (black dashed line) and 95% confidence interval of simulated data (grey area); (b) normalized

564 prediction distribution errors based on 1000 simulations associated with the final population

565 pharmacokinetic model versus time after dose; (c) observed versus population predicted

566 gentamicin serum concentrations and (d) conditional weighted residuals versus time after

567 dose associated with the final population pharmacokinetic model.

568

569 FIG 2 Visual predictive check plot based on 500 simulations associated with this studies final

570 population pharmacokinetic model and another three published population pharmacokinetic

571 models of gentamicin in children generated during external evaluation. Median, 95th and 5th

572 percentiles of observed data (red line), median, 95th and 5th percentiles of simulated data

573 (black dashed line) and 95% confidence interval of simulated data (grey area). The predictive

574 performance for each model is presented numerically with the relative root mean squared

575 error (RMSE %) and the mean relative prediction error (MRPE %).

576

577

25
Table 1. Demographic and clinical information of all patients included in model building and
evaluation analysis

Values
Patient characteristics Model building data Model evaluation

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n=423 data n=52
Total Body weight (kg) 19.4 (4.8 102.8) 22.2 (6.22 121)
Fat-free mass (kg) 15.7 (3.4 72.6) 20.5 (5.25 62.2)
Post-natal age (yrs) 5.18 (0.2 18.2) 7.86 (0.69 16.8)
Post-menstrual age (wks) 309 (50.9 985) 450 (76.0 916)
Height (cm) 110.2 (48.8 182.3) 127 (67.5 175)

No. of patients aged (yrs)

<2 73 (17.3%) 8 (15.4%)
2 10 247 (58.4%) 33 (63.5%)
> 10 103 (24.3%) 11 (21.1%)
Male/Female 219 (52%)/204 (48%) 22 (42%)/ 30 (48%)
Serum creatinine (mol/L)a 33.0 (21.0 204.0) 34.0 (21.5 359)
Serum creatinine (mol/L)b 42.0 (30.0 204.0) 43.0 (30.0 359)
2 c
Creatinine clearance (mL/min/1.73m ) 126 (11.5 225.2) 132 (9.08 186)
Gentamicin dosing regimen (mg/kg) 7.35 (0.80 15.0) 7.33 ( 1.98 10.8)
Time of sampling after dosing (hours) 6.50 (0.5 36.0) 3.34 (0.75 34.4)
Number of gentamicin concentration 2422 174
Gentamicin concentrations below the limit of
372 (15%) 16 (9%)
quantification
Patients who received nephrotoxic drugs
101 (24%) 6 (11.5%)
(cisplatin and carboplatin)

Values are represented as median (range) or number (%); a: serum creatinine concentration
below the lowest reportable limit set to an expected creatinine concentration physiological
mean (28); b: serum creatinine concentration above the lowest reportable limit; c: creatinine
clearance calculated using the Schwartz formula (44) with serum concentration below the
lowest reportable limit set to an expected creatinine concentration physiological mean (28).
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Table 2. Population pharmacokinetic parameter estimates of the base and the final model and bootstrap results from the final model

Parameter Base model Final model Bootstrap (n=1000) [mean (95 %CI)]

RSE BSV RSE BOV RSE Estimate RSE BSV RSE BOV RSE
Estimate Estimate BSV CV% BOV CV%
% CV% % CV% % % CV% % CV% %
Number of
26 27 27 - -
parameters

OFV 3460 2729 2704 (2239 3219) - -

CL (L/h) 2.08 3.02 43.8 5.53 24.3 3.93 CL (L/h/70kg) 5.77 1.78 16.0 9.91 20.7 2.15 5.76 (5.59 5.93) 16.0 (12.9 18.5) 20.8 (19.2 22.1)

V1 (L) 5.16 4.26 50.3 6.55 - - V1 (L/70kg) 21.6 2.86 21.5 17.8 - - 21.5 (20.3 22.6) 21.3 (13.7 27.1) -

Q (L/h) 0.22 6.76 - - - - Q (L/h/70kg) 0.62 4.98 - - - - 0.63 (0.57 0.68) - -

V2 (L) 3.34 15.7 73.5 15.4 - - V2 (L/70kg) 13.8 10.5 62.4 7.34 - - 13.5 (10.8 16.7) 60.9 (44.1 76.3) -
Covariate
model
SCR - - - - - - 0.55 8.84 - - - - 0.55 (0.47 0.63) - -
Correlations
(%)
CL~V1 93.6 6.55 - - - - 69.2 17.6 - - - - 69.1 (53.9 75.5) - -
Residual error
model (%)
Proportional 26.8 5.86 - - - - 27.5 3.47 - - - - 27.2 (24.8 30.1) - -
Additive
0.05 11.5 - - - - 0.04 15.1 - - - - 0.05 (0.03 0.06) - -
(mg/L)

BOV: between-occasion variability; BSV: between-subject variability; CL: clearance; CV: coefficient of variation; OFV: objective function
value; RSE: relative standard error; Q: intercompartmental clearance; Scr: serum creatinine; V1: apparent volume of distribution of the central
compartment; V2: apparent volume of distribution of the peripheral compartment.
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Final model:
.
GFR
CL L/h = .
Scr
FFM
V L = .
.
FFM
Q L/h = .

FFM
V L = .
.
FFM PMA .
GFR mL/min = . .

. + PMA

Where,
GFRmat: maturation of glomerular filtration rate; Scrmean: mean serum creatinine concentration calculated using a formula described by Ceriotti et
al. (28); Scri: individual patient serum creatinine concentration; FFM (kg): fat-free mass; PMA (weeks): post-menstrual age considering 40
weeks of gestation.
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Table 3. Summary of published population pharmacokinetic models of gentamicin identified for external evaluation

Body weight CLCR Between-

Number of Age (years),
(kg), (mL/min), subject Residual
Model patients Mean SD, Structural Parameter value and covariate
Mean SD, Mean SD, variability unexplained
(reference) (number of median model relationships included
Median Median (%) variability
samples) (Range),
(Range) (Range) [BOV %]
CL (L/h): 5.77 x (GFRmat/100) x (Scrmean/Scri)0.55 CL: 16.2 Prop (%): 27.5
423 (2422) V1: 21.5 Add (mg/L):
paediatric 5.18 (0.2 19.4 16.5 114.4 (11.5 V1 (L): 21.6 x (FFM/70)0.75
Final model 2 CMT V2: 62.4 0.04
oncology 18.2) (4.8 102.8) 206.5)
V2 (L): 13.8 x (FFM/70)0.75
patients
Q (L/h): 0.62 x (FFM/70)0.75
0.321
26 (96) CL (L/h): 1.15 x (PNA/PNAmedian) CL: 47.2 Prop (%): 24
1.72 1.33
M1 (16) Children with 7.10 2.40 NR 1 CMT 0.743
(0.25 5) Vd (L): 2.33 x (WT/WTmedian) Vd: 35.6
malnutrition
CL (L/h): 0.12 x WT + 0.06 x (CLCR/75) CL: 26.4 Prop (%): 11.2
208 (335) V1 (L): 0.35 x WT V1: 26.5
M2 (32) 0.46 0.40 6.4 2.2 76.7 36.9 2 CMT
Infants V2 (L): 2.3
Q (L/h): 0.23
0.14 0.75 Add (mg/L):
CL (L/h): 2.09 x (PNA/162) x (WT/70) CL: 52
50 (238) 0.76
Neonates, 0.44 (1 day V1 (L/kg): 0.35 x WT V1: 10.3
M3 (17) 4.8 (2 80) NR 2 CMT
infants and 15 years)
children V2 (L): 3.78
Q (L/h): 0.18

Add: additive error; BOV: between-occasion variability; CL: clearance of gentamicin; CLCR: creatinine clearance; CMT: compartmental model;
GFRmat: maturation of glomerular filtration rate using the Rhodin formula (24); FFM (kg): fat-free mass; NR: not reported; PNA (years): post-
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natal age; Prop: proportional error; Q: intercompartmental clearance; Scr: serum creatinine concentration; Scrmean: Scr standardised to an
expected creatinine concentration physiological mean (28) V1: central volume of distribution; V2: peripheral volume of distribution; WT (kg):
body weight.
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