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1 Population pharmacokinetics of gentamicin and dosing optimization for infants 1 Susanna E. Medellín-Garibay a# , Aída Rueda-Naharro b , Silvia Peña-Cabia b , Benito García b , 2 Silvia Romano-Moreno a , Emilia Barcia c 3 a Departamento de Farmacia, Facultad de Ciencias Químicas, Universidad Autónoma de 4 San Luis Potosí, Av. Manuel Nava # 6, Zip Code: 78210, San Luis Potosí, S.L.P. México; 5 b Servicio de Farmacia, Hospital Universitario Severo Ochoa, Avenida de Orellana, Zip Code: 6 28911 Leganés, España; c Departamento de Farmacia y Tecnología Farmacéutica, 7 Universidad Complutense de Madrid, Plaza de Ramón y Cajal, Ciudad Universitaria, Zip 8 Code: 28040, Madrid, España. 9 #Address correspondence to Susanna E. Medellín-Garibay, 10 E-mail: [email protected] 11 Phone: +52 (444) 8262300 xt. 6572 12 Fax: +52 (444) 8262372 13 Running title: Gentamicin population PK in infants 14 Key words: gentamicin, population pharmacokinetics, infants, NONMEM. 15 16 AAC Accepts, published online ahead of print on 10 November 2014 Antimicrob. Agents Chemother. doi:10.1128/AAC.03464-14 Copyright © 2014, American Society for Microbiology. All Rights Reserved. on January 29, 2018 by guest http://aac.asm.org/ Downloaded from

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Page 1: 1 Population pharmacokinetics of gentamicin and dosing

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Population pharmacokinetics of gentamicin and dosing optimization for infants 1

Susanna E. Medellín-Garibaya#, Aída Rueda-Naharrob, Silvia Peña-Cabiab, Benito Garcíab, 2

Silvia Romano-Morenoa, Emilia Barciac 3

aDepartamento de Farmacia, Facultad de Ciencias Químicas, Universidad Autónoma de 4

San Luis Potosí, Av. Manuel Nava # 6, Zip Code: 78210, San Luis Potosí, S.L.P. México; 5

bServicio de Farmacia, Hospital Universitario Severo Ochoa, Avenida de Orellana, Zip Code: 6

28911 Leganés, España; cDepartamento de Farmacia y Tecnología Farmacéutica, 7

Universidad Complutense de Madrid, Plaza de Ramón y Cajal, Ciudad Universitaria, Zip 8

Code: 28040, Madrid, España. 9

#Address correspondence to Susanna E. Medellín-Garibay, 10

E-mail: [email protected] 11

Phone: +52 (444) 8262300 xt. 6572 12

Fax: +52 (444) 8262372 13

Running title: Gentamicin population PK in infants 14

Key words: gentamicin, population pharmacokinetics, infants, NONMEM. 15

16

AAC Accepts, published online ahead of print on 10 November 2014Antimicrob. Agents Chemother. doi:10.1128/AAC.03464-14Copyright © 2014, American Society for Microbiology. All Rights Reserved.

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ABSTRACT 17

The aim of this study is to characterize and validate the population pharmacokinetics of 18

gentamicin in infants and to determine the influence of clinically relevant covariates to 19

explain the inter- and intra-individual variability associated to this drug. Infants receiving 20

IV gentamicin and with routine therapeutic drug monitoring were consecutively enrolled 21

in the study. Plasma concentration and time data were retrospectively collected from 208 22

infants (1-24 months old) of the Hospital Universitario Severo Ochoa (Spain) of whom 44% 23

were males (mean age 5.8 ± 4.8 months and mean body weight 6.4 ± 2.2 kg). Data analysis 24

was performed with NONMEM 7.2. One- and two-compartment open models were 25

analyzed to estimate gentamicin population parameters and the influence of several 26

covariates. External validation was carried out in another population of 55 infants. 27

The behavior of gentamicin in infants exhibits two-compartment pharmacokinetics with 28

total body weight being the covariate which mainly influences central volume (Vc) and 29

clearance (CL); this parameter was also related to creatinine clearance. Both parameters 30

are age-related and different to those reported for neonatal populations. 31

On the basis of clinical presentation and diagnosis, a once-daily dosage regimen of 7 32

mg/kg every 24 hours is proposed for IV gentamicin, followed by therapeutic drug 33

monitoring to avoid toxicity and ensure efficacy with minimal blood sampling. 34

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Gentamicin pharmacokinetics and disposition was accurately characterized in this 35

pediatric population (infants), with the parameters obtained being different to those 36

reported for neonates and children. These differences should be considered for dosing 37

and therapeutic monitoring of this antibiotic. 38

39

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INTRODUCTION 40

Aminoglycosides are among the most commonly used broad-spectrum antibiotics 41

in the anti-infective therapy (1, 2). Despite their potential for renal toxicity, ototoxicity, 42

and bacterial resistance, several aminoglycosides continue to play an important role when 43

treating infections (3, 4). Among aminoglycosides, gentamicin is one of the most 44

commonly used due to its low cost and broad-spectrum efficacy (5, 6). Gentamicin is 45

commonly used to treat infections due to both gram-negative and gram-positive bacilli 46

such as E. coli, Proteus, Pseudomonas, Serratia, and Staphylococcus. Other clinical 47

applications of gentamicin include infections in the CNS, respiratory, abdominal and 48

urinary systems, bone, skin and soft tissues, endocarditis, and septicemia; being used in 49

combination with ampicillin as empiric therapy for sepsis in newborns and infants (7). 50

Drug pharmacokinetics and disposition are different in pediatric patients when 51

compared to adults (8). In this context, the Food and Drug Administration (FDA) 52

considering the complex changes and the anatomic, biochemical and physiological 53

differences related to age, proposed to classify pediatric populations as neonate (from 54

birth to 1 month of life); infant (between 1 and 24 months); child and adolescent (9). 55

Growth, development and maturation of enzymatic processes are features with marked 56

physiological influence from birth to adult age (10). For these reasons, pharmacokinetic 57

differences found between newborns and adults justify the need for the performance of 58

pharmacokinetic studies especially during the first months of life. For instance, in very 59

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premature neonates (gestational age <32 weeks), the pharmacokinetic characteristics of 60

antibiotics may vary from that in full-term neonates due to differences in drug absorption, 61

distribution, metabolism, and excretion; being all these processes rapidly developed 62

during the first year of life (11, 12). 63

In adults dosage regimens for gentamicin have evolved from multiple daily dosing 64

to extended-interval dosing. This change has also being applied to establishing gentamicin 65

dosing in pediatrics (1, 5, 13, 14). However, its pharmacokinetics in infants exhibits large 66

inter- and intra-individual variability mainly due to the developmental changes occurring 67

from the first month of life (15). In clinical practice individualization of dosage regimens 68

and monitoring of gentamicin concentrations are routinely performed in order to assure 69

peak blood concentrations sufficiently high to elicit the therapeutic response while 70

avoiding high trough concentrations which would be potentially toxic after prolonged drug 71

exposure (11, 16, 17). 72

Non-linear mixed-effects modelling methodology was introduced to population 73

pharmacokinetic analysis several years ago, and has become a standard procedure 74

employed to analyze sparse data (18). This situation applies to data collected from infant 75

populations where usually only one or two blood serum concentrations can be reasonably 76

obtained in clinical practice. A recent review conducted on population pharmacokinetic 77

analyses performed during the first two years of life showed antibiotics as the drug class 78

most cited (44%), with vancomycin and gentamicin representing the two agents most 79

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studied. Age was one of the covariates more frequently evaluated during pharmacokinetic 80

analysis. The majority of the studies were conducted on populations composed of 25-100 81

neonates with a post-natal age (PNA) ranging from the first day of life to 1 month (19). 82

It was therefore the purpose of this study to calculate the population 83

pharmacokinetic parameters of gentamicin in a large population of infants (age range 1 – 84

24 months) and to validate the predictive performance of the population analysis in 85

another population with the same characteristics, in order to establish the most 86

appropriate dosage regimens to maximize safety and efficacy of gentamicin in infants. 87

PATIENTS AND METHODS 88

Infants from 1 to 24 months of age receiving gentamicin by intravenous infusion 89

were included in the current study with routine therapeutic drug monitoring (TDM) in the 90

Hospital Universitario Severo Ochoa (Leganes, Spain) between 1990 and 2011. Data 91

collection and handling was performed according to the ethical procedures of the hospital. 92

Total population was divided into two groups: one composed of 208 infants which 93

was used to build the population pharmacokinetic model (population study group), and 94

the other composed of 55 infants (validation study group), used for validating the 95

predictive performance of the former. Assignation of the infants to each group was carried 96

out randomly. 97

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The following data were collected from each infant’s medical record: age, sex, 98

weight, height, serum creatinine (CRs), creatinine clearance (CLCR) and body mass index 99

(BMI). CRs was used to estimate the CLCR of gentamicin by the Schwartz equation: CLCR = K 100

· length/CRs, where K is set to 0.45 for term infants whose weight is appropriate for age; 101

to 0.33 for low weight infants; and to 0.55 for infants over one year (7, 20). This formula 102

applies to alkaline picrate ("Jaffe") methods, even those traceable to IDMS, as applied for 103

the current work for CRs measurement. Details of gentamicin administration was also 104

retrieved from each patient’s record (doses, start of infusion, infusion rate, dosing 105

interval) as well as data from TDM (serum sampling date and time, as well as assay 106

concentration). 107

Administration of gentamicin was performed by means of IVAC-syringe pump (IVAC 108

corp., USA) as intravenous infusions given over a period of 20 min. The empirical dosing 109

regimen for infants is 2.5 mg/kg/8h or 4.5 – 7.5 mg/kg/24 h (7). Nevertheless, infants who 110

received doses of 7 mg/kg or more and had a sample drawn one hour after the start of the 111

infusion were excluded (21). 112

Gentamicin analysis 113

Gentamicin serum concentrations were determined by fluorescence polarization 114

immunoassay (Abbott TDx, Abbott Park, IL, USA). Calibration curves for gentamicin in 115

human serum ranged from 0.5 mg/L to 10 mg/L, with a coefficient of variation of 1.4% for 116

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the concentration of 4 mg/L. The intra- and inter-day coefficients of variation of the 117

method were 4.3% and 5.3%, respectively. All plasma concentrations below the limit of 118

quantification were not considered for the population analysis. 119

Pharmacokinetic analysis 120

Pharmacokinetic modeling was performed using nonlinear mixed effects analysis 121

with NONMEM 7.2 (Icon Development Solution, Ellucott City, MD, USA). Subroutines 122

ADVAN1 TRANS2 and ADVAN3 TRANS4 were used to evaluate the one- and two-123

compartment pharmacokinetic open models, respectively. First-order conditional 124

estimation (FOCE) was employed to calculate the mean and variance of the population 125

pharmacokinetic parameters. Fixed-effects parameters directly estimated from the one- 126

compartment open model were total clearance (CL) and volume of distribution (Vd). For 127

the two-compartment open model the pharmacokinetic parameters estimated were total 128

clearance (CL), central volume of distribution (Vc), intercompartmental clearance (Q), and 129

peripheral volume of distribution (Vp). 130

The statistical models used to account for inter-individual variability in the 131

pharmacokinetic parameters as well as for the residual error were modeled with 132

homocedastic (additive), heterocedastic (proportional) and exponential error. 133

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The Akaike information criterion (AIC) was calculated based on the objective 134

function (OBJ) for comparing structural models; a drop of 2 was the threshold for 135

considering one model over another (AIC = OBJ · np; where np is the total number of 136

parameters in the model). Graphical analysis and a generalized additive model (GAM) 137

were employed to evaluate the influence of covariates on the population pharmacokinetic 138

parameters estimated from both base pharmacokinetic models. Covariates were 139

introduced into population model using linear, allometric or exponential functions. 140

Changes occurring in the OBJ and due to the addition of covariates in the regression 141

model are χ2 asymptotically distributed, with degrees of freedom equal to the difference 142

in the number of parameters between models. A difference (ΔOBJ) higher than 3.8 (P 143

<0.05, d.f. = 1) was considered significant for the addition of a covariate. An intermediate 144

model was obtained by first adding the continuous covariates that showed influence on 145

the base model, and keeping only those that significantly diminished OBJ as mentioned 146

before. Each covariate was added individually; firstly the most important ones with the 147

rest of them being added or dropped following the same criteria. The model was selected 148

when no further improvement occurred. Finally, the discrete covariate with influence over 149

the intermediate model was selected as mentioned before, followed by graphical 150

assessment. Evaluation of the final model was performed by means of backward 151

elimination in which each of the covariates was deleted in the same order as it was 152

introduced in the model, and considering ΔOBJ>10.836 (P<0.001, d.f.=1) as significant. 153

Therefore, clinically relevant covariates that explain inter-individual variability showing a 154

significant contribution to the estimation of the fixed parameters were kept (18, 22). 155

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The precision of the parameter estimate is expressed as the standard error (SE) 156

reported in the covariance tables given by NONMEM. The confidence intervals were 157

estimated as parameter value ± 1.96 · SE. 158

Bootstrap was performed with 200 replicates to report the confidence intervals (CI) 159

for each parameter; the 95% CI must cover the true value of the parameter estimated to 160

prove the stability of the final model (18). 161

Validation 162

External validation was carried out in a separate group of infants (n=55) with 163

similar characteristics to the population study group. The predictive performance of the 164

population pharmacokinetic model was evaluated using a priori method. Gentamicin 165

serum concentrations of the validation group were compared to their predicted values in 166

order to estimate the precision of the population model built. The bias fit was evaluated 167

by means of the mean prediction error (MPE). Precision was estimated by means of the 168

absolute prediction error (APE), the mean-squared prediction error (MSPE), and the root-169

mean-squared of the prediction error (RMSPE) (23, 24). 170

171

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RESULTS 172

Demographics 173

The population study group was composed of 208 infants and 55 infants in the 174

validation study group. Considering both populations 56% were females and 44% males. 175

Demographic characteristics of the groups assayed (population study group and validation 176

study group) are summarized in Table 1. 177

[Insert Table 1] 178

Both populations were classified by weight according to age (months) and sex 179

following the WHO child growth standards (25); 12.1% of the infants were 1 – 11 months 180

old with low BW and were classified as INF = 0; 72.9% of the infants were 1 – 11 months 181

old with normal BW (INF = 1); and 15 % were infants over one year old with normal BW 182

(INF = 2). 183

In the Hospital Universitario Severo Ochoa, different dosage regimens were used 184

along the period studied, with mean gentamicin doses of 6.0 ± 1.5 mg/kg/day and 5.5 ± 185

1.2 mg/kg/day for the population and validation study group, respectively. In the 186

population study group 4 infants received mean gentamicin doses of 2.3 mg/kg/6 h (total 187

daily d 188

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189

ose 9.4 mg/kg), 98 received mean doses of 2.3 mg/kg/8 h (total daily dose 6.8 190

mg/kg), 3 received 3.05 mg/kg/12 h (total daily dose 6.1 mg/kg), and the rest (103 infants) 191

received single daily doses of 4.8 mg/kg. Regarding the validation study group (n=55), 26 192

infants received mean doses of 2.1 mg/kg/8 h (total daily dose 6.4 mg/kg/24h) whereas 29 193

infants received single daily doses of 4.6 mg/kg. As indicated before, mean doses of 6.0 ± 194

1.5 mg/kg/day and 5.5 ± 1.2 mg/kg/day were given to both population and validation 195

study groups, respectively. 196

For both populations a total of 421 serum gentamicin concentrations were 197

available, ranging from 1 to 6 gentamicin serum concentrations per infant. Of these, 335 198

serum concentrations corresponded to the population study group and 86 to the 199

validation study group. For most infants (96.2%), one or two gentamicin serum 200

concentrations were obtained; of these 45% had one and 51.2% two. 201

Figure 1 shows the number of gentamicin serum concentrations obtained related 202

to blood sampling times. A total of 335 gentamicin serum concentrations were available 203

from the population study group. Gentamicin serum concentrations ranged 0.5 – 15.9 204

mg/L with a mean value of 4.8 mg/L. Blood sampling times ranged from 1 to 321 hours 205

(mean 56.3 h); 8.6% of the samples were collected within the first 24 hours, 66.1% 206

between 24 and 72 hours, and 25.2% from 72 to 321 hours. 207

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[Insert Figure 1] 208

Base pharmacokinetic models and covariate addition 209

The first pharmacokinetic model evaluated was the one-compartment open model 210

with exponential inter-individual variability associated to both CL (Ө1) and Vd (Ө2). 211

Residual variability was modeled as homocedastic (additive) error. For this model OBJ was 212

564.3. 213

When using a two-compartment open model OBJ decreased 43.5 units when 214

compared to the one-compartment open model. This difference in OBJ corresponds to a P 215

value lower than 0.005 (χ2 is assumed). Table 2 summarizes the pharmacokinetic 216

parameters estimated with both pharmacokinetic models (one- and two-compartment 217

open models). 218

[Insert Table 2] 219

Initially, the influence of covariates was evaluated with the one-compartment 220

model in which CL and Vd were assumed to be the same for all individuals in the 221

population study group; then the two-compartment open model was evaluated assuming 222

the same for CL, Vc, Vp and Q. When applying the two-compartment open model ΔOBJ 223

was statistically significant but the coefficients of variation (CVs%) obtained for residual 224

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variability differ slightly (0.2%) from both pharmacokinetic models, with CVs (%) of inter-225

individual variability associated to both CL and Vd being higher for the two-compartment 226

open model. Table 3 summarizes the population parameters and inter-individual 227

variability values obtained for the final pharmacokinetic models. 228

[Insert Table 3] 229

For the one-compartment open model the influence of BW on Vd was evaluated, 230

taking into consideration in this analysis the classification of the population study group 231

according to differences in age and BW as stated previously. For this analysis inter-232

individual variability associated to Vd was significantly reduced. When introducing CLCR in 233

the base one-compartment model, a significant reduction of the inter-individual variability 234

associated to CL was also observed. However, sex as covariate did not have any influence 235

on the performance of the model. 236

When applying the same choice of covariates to the two-compartment model the 237

influence of both BW and CLCR on CL and Vc was demonstrated. In this case the inter-238

individual variability associated to CL and Vc is significantly reduced with independence of 239

the characteristics (age and BW) of the infants (population study group). The shrinkage for 240

inter-individual and residual variability obtained for the final two-compartment model was 241

29 – 17% and 48%, respectively. 242

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Figure 2 shows the scatters plots of predicted (PRED) versus observed (DV) 243

gentamicin concentrations for the base and final two-compartment open models. As it can 244

be observed the introduction of covariates in the model clearly reduced the dispersion of 245

the points around the identity line. Moreover, the scatter plots of conditional weighed 246

residuals (CWRES) versus BW (including the identity line) are also shown demonstrating 247

the influence that BW has on the pharmacokinetic model. The incorporation of BW to CL 248

and Vd improves the goodness of fit for the group of infants with low BW for whom initial 249

overestimation occurred as for infants with normal BW for whom underestimation was 250

initially obtained. 251

[Insert Figure 2] 252

After the selection of the final model, a bootstrap analysis was performed with 200 253

replicates from the original dataset to adequately reflect the parameter distributions. The 254

results obtained are summarized in Table 3. In this table the same number of the fixed 255

parameters (Ѳ) corresponding to the final two-compartment open model with covariates 256

are indicated as median and 95% IC. The percentile bootstrap CI reported covers the mean 257

values shown in Table 3 for each parameter, which reflects the symmetry of the 258

distribution and allows assuming stability in the final model. 259

Validation 260

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A recent literature review found that validations of PK models are only performed 261

in 17% of PK-PD published pediatric studies and in 28% of adult studies however, 262

adequate model validation is essential in model building (26). The characteristics of the 263

validation group are summarized in Table 1. The validation study group was composed of 264

55 infants whose mean age was 5.5 ± 4.4 months, similar to that of the population study 265

group. Mean BW was 6.7 ± 2.3 kg. 266

Figure 3 shows the scatter plot of predicted versus observed gentamicin 267

concentrations corresponding to the validation group and obtained for the final two-268

compartment open model. Table 4 summarizes the mean prediction errors obtained from 269

the validation of the final model when compared to those corresponding to the base 270

model. 271

[Insert Figure 3] 272

[Insert Table 4] 273

Mean prediction errors (MPE) for the two-compartment model include zero in the 274

95% CI, thereby indicating that from a statistical point of view the model is not 275

conditioned to over- or under-estimation. 276

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It can be observed a decrease in the difference obtained between the upper and 277

lower limits of the 95% CI when comparing the final model to the base one, thereby 278

indicating higher precision of the model. This is also confirmed by the APE (absolute 279

precision error) value obtained. Similarly, MSPE (mean-squared prediction error) and 280

RMPSE (root-mean-squared prediction error) are clearly reduced, thereby confirming the 281

improvement of precision obtained in the prediction of the final pharmacokinetic model. 282

DISCUSSION 283

A population pharmacokinetic analysis of gentamicin in infants was performed in 284

order to define the disposition of aminoglycosides in newer populations that have not 285

been already recorded in the literature. This population of infants exhibit different 286

characteristics than newborns or adults (13, 27, 28). In the current study the population 287

pharmacokinetic parameters of gentamicin have been retrospectively estimated by 288

NONMEM 7.2 in a total population of 263 infants who were admitted to the Hospital 289

Universitario Severo Ochoa (Leganés, Spain) between the years 1990 and 2011 and that 290

received gentamicin as part of their treatment. 291

Both one- and two-compartment pharmacokinetic models can adequately describe 292

the pharmacokinetics of gentamicin in infants. However the two-compartment open 293

model showed improved goodness of fit to represent the disposition of gentamicin in the 294

population studied. Previous reports have also proposed the use of the two-compartment 295

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model to describe the pharmacokinetic behavior of gentamicin in different populations of 296

infants (27, 28). 297

In order to explain the variability found, physiological variables (BW, height, age, 298

sex and CLCR) were analyzed to evaluate their influence on the pharmacokinetic 299

parameters of gentamicin. BW exhibited the highest correlation which was followed by 300

CLCR. Gentamicin CL and Vd are different in infants when compared to adults, showing a 301

wide inter-individual variability. 302

This difference can be attributed to several factors that contribute to modify the 303

distribution of gentamicin, such as protein binding, blood flow to tissues, membrane 304

permeability and drug affinity for different tissues (27-29). The fact that gentamicin is a 305

polar compound with low plasma protein binding (<30%) makes its Vd directly related to 306

extracellular body fluid (5). In this respect and during the first two years of life, 307

compartmentalization of body water changes continuously; total body water decreases 308

and adipose tissue increases (29), resulting in higher volume of distribution in newborns 309

and infants that in older children. BW also increases significantly during the first year of 310

life; therefore the introduction of such covariate in the population pharmacokinetic 311

analysis allows for the comparison of Vd with other populations. The mean value obtained 312

for this parameter is in accordance with other studies, being lower than that reported for 313

adult populations (0.28 L/kg) and higher than that given for newborns (0.48 L/kg) (27, 28). 314

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Touw et al., have demonstrated that normalization of gentamicin Vd by BW 315

(Vd/kg) clearly decreases with age (11). After applying the two-compartment open model 316

to our population, differences in Vd are not observed, probably due to the age range of 317

the population assayed (1-2 years). Despite this fact, in the current study Vd was 318

determined for a population which has not been previously described in the literature 319

since most studies are carried out in populations ranging from 6 months to 4 years or up 320

to 18 years of age (30, 31). Differences in gentamicin Vd by age were not found when 321

applying the two-compartment pharmacokinetic model, which simplifies the population 322

model by considering only total BW. 323

The categorical variable sex did not exert any influence on the pharmacokinetic 324

parameters of gentamicin, which is in accordance with other studies that have 325

demonstrated that creatinine serum concentration and muscular body mass do not 326

exhibit significant differences between males and females before the adolescence age 327

(20). The variability found in Vd makes the need for monitoring plasma gentamicin 328

concentrations in order to improve its efficacy and avoid the toxicity effects associated to 329

aminoglycosides. 330

Gentamicin is excreted by the kidneys mainly by glomerular filtration, with 50-93% 331

of the drug recovered in urine 24 hours after administration in individuals with renal 332

impairment. Due to the immaturity of the newborns most of the processes involved in 333

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renal excretion of drugs require several weeks to more than one year to reach maturity 334

thereby influencing the disposition of polar drugs, such as gentamicin (10, 11, 19). 335

For the current population the mean value of gentamicin CL obtained is 0.12 ± 0.01 336

L/h/kg, and comparable to that reported by Taketomo et al. which was 0.1 L/h/kg (7). 337

Drug clearance mainly depends on the functional capacity of the kidneys as well as renal 338

blood flow which increases from 12 mL/min at birth up to 140 mL/min at around one year 339

of age. In this population of infants, CL is influenced by both BW and CLCR. 340

Dosing and TDM recommendations 341

Through the estimation of the pharmacokinetic parameters of gentamicin and their 342

variability it is feasible to propose a dosing scheme based on simulations using the model 343

generated from our infant population. Once-daily dosing is preferred to avoid toxicity. In 344

order to reach a peak value greater than 10 mg/L a dose of 7 mg/kg of gentamicin should 345

be given followed by serum concentration monitoring. According to the simulated 346

population, 6–10 hours after starting the infusion gentamicin concentrations ranging 0.8-2 347

mg/L will be expected. This time range is optimal to ensure detectable serum 348

concentrations of gentamicin; 70% of the simulated infants were over the limit of 349

quantification (0.5 mg/L) of routinely used immunoassays. In fact, the Cmax should not be 350

measured until 2 hours after a 30 minutes infusion to ensure post-distributional samples 351

in 7 mg/kg once daily dosing (21). Despite the post-antibiotic effect, trough serum 352

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concentrations < 0.5 mg/L should not last for more than 6 – 8 hours to ensure optimal 353

efficacy of this antibiotic (13, 14, 16, 32). 354

Figure 4 shows mean gentamicin plasma concentrations and percentiles 5 – 95% 355

corresponding to one thousand simulations obtained for the final two-compartment 356

model as generated by NONMEM and using data obtained from a standard infant 6 357

months old, 8 kg of BW, CRs of 0.4 mg/dL, and receiving 7 mg/kg/24 h of gentamicin IV. 358

Data from simulated low-weight 1-month old infant and low Crs 6-months old infant are 359

also shown in the same figure, were median values for plasmatic concentrations are no 360

significantly different from those obtained by a standard infant receiving the same dose. 361

[Insert Figure 4] 362

CONCLUSION 363

For infants, IV gentamicin is best represented by two-compartment 364

pharmacokinetics where total body weight and creatinine clearance exhibit influence on 365

volume of distribution and clearance of the drug. It was feasible to distinguish differences 366

between neonates and infants making it possible to individualize dosage regimens for this 367

population. The dosing scheme proposed is a once-daily dosage of 7 mg/kg followed by 368

therapeutic drug monitoring to avoid toxicity and ensure efficacy with minimal blood 369

sampling.370

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ACKNOWLEDGMENTS 371

The authors acknowledge the assistance of the pharmacists, analytical technicians, 372

nurses and medical staff of the Hospital Universitario Severo Ochoa (Leganés, Spain) for 373

their contributions to the present study. 374

FUNDING 375

This study was conducted as part of routine work; no external funding was 376

received to support the current study. Financial support was given to Medellín-Garibay SE 377

by the National Research Council of Science and Technology (CONACYT) from Mexico 378

during her research stay performed in Spain (309952). 379

The authors declare no conflict of interest. 380

381

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REFERENCES 382

1. Jackson J, Chen C, Buising K. 2013. Aminoglycosides: how should we use them 383

in the 21st century? Current opinion in infectious diseases 26:516-525. 384

2. Kumana CR, Yuen KY. 1994. Parenteral aminoglycoside therapy. Selection, 385

administration and monitoring. Drugs 47:902-913. 386

3. Warchol ME. 2010. Cellular mechanisms of aminoglycoside ototoxicity. Current 387

opinion in otolaryngology & head and neck surgery 18:454-458. 388

4. Huth ME, Ricci AJ, Cheng AG. 2011. Mechanisms of aminoglycoside ototoxicity 389

and targets of hair cell protection. International journal of otolaryngology 390

2011:937861. 391

5. Gilbert DN. 2005. Aminoglycosides, p. 307-336. In Mandell GL BJ, Dolin R (ed.), 392

Principles and Practice of Infectious Diseases, 6th ed, Churchill Livingstone, New 393

York. 394

6. Dobie RA, Black FO, Pezsnecker SC, Stallings VL. 2006. Hearing loss in patients 395

with vestibulotoxic reactions to gentamicin therapy. Archives of otolaryngology--396

head & neck surgery 132:253-257. 397

7. Taketomo CK, Hodding JH, Kraus DM. 2013. p. 787-790, The Pediatric & 398

Neonatal Dosage Handbook, 20th ed. Leximcomp, Hundson, Ohio. 399

8. Anderson BJ, Holford NH. 2009. Mechanistic basis of using body size and 400

maturation to predict clearance in humans. Drug metabolism and pharmacokinetics 401

24:25-36. 402

on January 29, 2018 by guesthttp://aac.asm

.org/D

ownloaded from

Page 24: 1 Population pharmacokinetics of gentamicin and dosing

24

9. Administration FaD. 1998. General Considerations for Pediatric Pharmacokinetic 403

Studies for Drugs and Biological Products. In Services USDoHaH (ed.), Rockville, 404

MD. 405

10. Anderson GD, Lynn AM. 2009. Optimizing pediatric dosing: a developmental 406

pharmacologic approach. Pharmacotherapy 29:680-690. 407

11. Touw DJ, Westerman EM, Sprij AJ. 2009. Therapeutic drug monitoring of 408

aminoglycosides in neonates. Clinical pharmacokinetics 48:71-88. 409

12. Milsap RL, Jusko WJ. 1994. Pharmacokinetics in the infant. Environmental health 410

perspectives 102 Suppl 11:107-110. 411

13. Best EJ, Gazarian M, Cohn R, Wilkinson M, Palasanthiran P. 2011. Once-daily 412

gentamicin in infants and children: a prospective cohort study evaluating safety and 413

the role of therapeutic drug monitoring in minimizing toxicity. The Pediatric 414

infectious disease journal 30:827-832. 415

14. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. 2004. 416

Extended-interval aminoglycoside administration for children: a meta-analysis. 417

Pediatrics 114:e111-118. 418

15. Rakhmanina NY, van den Anker JN. 2006. Pharmacological research in 419

pediatrics: From neonates to adolescents. Advanced drug delivery reviews 58:4-14. 420

16. Dersch-Mills D, Akierman A, Alshaikh B, Yusuf K. 2012. Validation of a dosage 421

individualization table for extended-interval gentamicin in neonates. The Annals of 422

pharmacotherapy 46:935-942. 423

17. Turnidge J. 2003. Pharmacodynamics and dosing of aminoglycosides. Infectious 424

disease clinics of North America 17:503-528, v. 425

on January 29, 2018 by guesthttp://aac.asm

.org/D

ownloaded from

Page 25: 1 Population pharmacokinetics of gentamicin and dosing

25

18. Mould DR, Upton RN. 2013. Basic concepts in population modeling, simulation, 426

and model-based drug development-part 2: introduction to pharmacokinetic 427

modeling methods. CPT: pharmacometrics & systems pharmacology 2:e38. 428

19. Marsot A, Boulamery A, Bruguerolle B, Simon N. 2012. Population 429

pharmacokinetic analysis during the first 2 years of life: an overview. Clinical 430

pharmacokinetics 51:787-798. 431

20. Schwartz GJ, Haycock GB, Edelmann CM, Jr., Spitzer A. 1976. A simple 432

estimate of glomerular filtration rate in children derived from body length and 433

plasma creatinine. Pediatrics 58:259-263. 434

21. Demczar DJ, Nafziger AN, Bertino JS, Jr. 1997. Pharmacokinetics of gentamicin 435

at traditional versus high doses: implications for once-daily aminoglycoside dosing. 436

Antimicrobial agents and chemotherapy 41:1115-1119. 437

22. Mould DR, Upton RN. 2012. Basic concepts in population modeling, simulation, 438

and model-based drug development. CPT: pharmacometrics & systems 439

pharmacology 1:e6. 440

23. Sheiner LB, Beal SL. 1981. Some suggestions for measuring predictive 441

performance. Journal of pharmacokinetics and biopharmaceutics 9:503-512. 442

24. Williams PJ, Kim YH, Ette EI. 2007. The Epistemology of Pharmacometrics, p. 443

223-245. In Ette EI, Williams PJ (ed.), Pharmacometrics: the science of quantitative 444

pharmacology. John Wiley & Sons, New Jersey, U.S.A. 445

25. Organization WH. 2006. WHO Multicentre Growth Reference Study Group. 446

WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-447

length, weight-for-height and body mass index-for-age: Methods and development. 448

on January 29, 2018 by guesthttp://aac.asm

.org/D

ownloaded from

Page 26: 1 Population pharmacokinetics of gentamicin and dosing

26

26. De Cock RF, Piana C, Krekels EH, Danhof M, Allegaert K, Knibbe CA. 2011. 449

The role of population PK-PD modelling in paediatric clinical research. European 450

journal of clinical pharmacology 67 Suppl 1:5-16. 451

27. Xuan D, Nicolau DP, Nightingale CH. 2004. Population pharmacokinetics of 452

gentamicin in hospitalized patients receiving once-daily dosing. International 453

journal of antimicrobial agents 23:291-295. 454

28. Garcia B, Barcia E, Perez F, Molina IT. 2006. Population pharmacokinetics of 455

gentamicin in premature newborns. The Journal of antimicrobial chemotherapy 456

58:372-379. 457

29. Koren G. 1997. Therapeutic drug monitoring principles in the neonate. National 458

Academy of CLinical Biochemistry. Clinical chemistry 43:222-227. 459

30. Miron D. 2001. Once daily dosing of gentamicin in infants and children. The 460

Pediatric infectious disease journal 20:1169-1173. 461

31. Bass KD, Larkin SE, Paap C, Haase GM. 1998. Pharmacokinetics of once-daily 462

gentamicin dosing in pediatric patients. Journal of pediatric surgery 33:1104-1107. 463

32. Kraus DM, Pai MP, Rodvold KA. 2002. Efficacy and tolerability of extended-464

interval aminoglycoside administration in pediatric patients. Paediatric drugs 4:469-465

484. 466

467

468

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TABLES 469

Table 1. General characteristics of the populations assayed. 470

Variable

Population group

(n=208)

Validation group

(n=55)

Age (months) 5.8 ± 4.8 5.5 ± 4.4

BW (kg) 6.4 ± 2.2 6.7 ± 2.3

Height (cm) 62.6 ± 9.1 62.8 ± 8.8

BMI (kg/m2) 15.8 ± 2.1 16.5 ± 2.7

CRS (mg/dL) 0.42 ± 0.1 0.44 ± 0.2

CLCR (mL/min/1.73 m2) 76.7± 36.9 76.7 ± 44.3

Data are shown as mean ± standard deviation. BW (body weight), BMI (body mass 471

index), CRS (serum creatinine), CLCR (creatinine clearance). 472

473

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Table 2. Pharmacokinetic parameters and inter-individual variability values obtained for 474

the base two-compartment open model without the inclusion of covariates. 475

PK MODEL PARAMETER Mean ± SE

Two-compartment open model (OBJ = 520.85) (AIC = 528.85)

CL (L/h) Ө1 0.83 ± 0.05

Vc (L) Ө2 1.9 ± 0.06

Q (L/h) Ө3 0.31 ± 0.06

Vp (L) Ө4 4.9 ± 1.0

Interindividual variability associated to CL (%)

ω2CL 59.3 ± 22.4

Interindividual variability associated to Vc (%)

ω2Vc 43.8 ± 14.1

Residual variability (%) σ 12.0 ± 4.0

476

477

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Table 3. Pharmacokinetic parameters and interindividual variability values obtained for 478

the final two-compartment open model and Bootstrap results (n = 200). 479

PK MODEL PARAMETER MEAN ± SE BOOTSTRAP

MEDIAN PERCENTILES

Two-compartment open model (OBJ = 197.27) 2.5th 97.5th

CL = Ө1*BW+ Ө5 * (CLCR/75) (L/h•kg)

Ө1 0.12 ± 0.01 0.12 0.09 0.13

Ө5 0.06 ± 0.11 0.10 0.007 0.24

Vc = Ө2 * BW (L/kg) Ө2 0.35 ± 0.02 0.34 0.27 0.37

Q (L/h) Ө3 0.23 ± 0.05 0.24 0.15 0.45

Vp (L) Ө4 2.3 ± 1.0 2.9 1.3 6.7

Interindividual variability associated to CL

ω2CL 26.4 ± 14.1 28.3 22.4 34.6

Interindividual variability associated to Vc

ω2Vc 26.5 ± 14.0 24.5 20.0 33.2

Residual variability σ 11.2 ± 2.9 11.0 8.1 12.5

480

481

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Table 4. Mean (± standard deviation) prediction errors and 95% CIs estimated for the 482

validation group with the base and final two-compartment open model. 483

484

Base model

Mean ± SD

(95% CI)

Final model

Mean ± SD

(95% CI)

MPE 0.3± 2.5

(-0.3, 0.8)

-0.2 ± 1.5

(-0.6, 0.1)

APE 1.6 ± 1.9

(1.2, 2.0)

0.9 ± 1.2

(0.7, 1.2)

MSPE 6.1 ± 11.6

(3.6, 8.1)

2.3 ± 5.7

(1.0, 3.5)

RMSE 2.5

(1.9, 2.8)

1.5

(1.0, 1.9)

MPE (mean prediction error), APE (absolute prediction error), MSPE 485

(mean-squared prediction error), RMSE (root-mean-squared prediction 486

error). 487

488

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FIGURES 489

490

Figure 1. Gentamicin serum concentrations versus blood sampling times (n = 335) for the 491

population study group. 492

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493

494

Figure 2. Scatter plots of predicted (PRED) versus observed (DV) gentamicin 495

concentrations (including the identity line) for the base (a) and final (b) two-compartment 496

open model. Scatter plots of conditional weighed residuals (CWRES) versus BW (including 497

the identity line) for the base (c) and final (d) two-compartment open model, and 498

corresponding to the population study group. 499

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500

Figure 3. Scatter plot of predicted (PRED) versus observed (OBS) gentamicin 501

concentrations corresponding to the validation group and obtained for the final two-502

compartment open model. 503

504

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505

506

Figure 4. Plasma concentrations shown as median and 5 – 95% percentiles for a 6-months 507

old infant receiving 7 mg/kg of gentamicin IV. Median values for a simulated 1-month old 508

infant with low BW; and data from simulated infant with low Crs are also depicted (n = 509

1000 infants simulated for each situation). 510

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