Eur J Clin Pharmacol (2009) 65:705713 DOI 10.

1007/s00228-009-0637-4

PHARMACOKINETICS AND DISPOSITION

Individualised dosing of amikacin in neonates: a pharmacokinetic/pharmacodynamic analysis

Catherine M. T. Sherwin & Sofia Svahn & Antje Van Der Linden & Roland S. Broadbent & Natalie J. Medlicott & David M. Reith

Received: 9 January 2009 / Accepted: 11 February 2009 / Published online: 21 March 2009 # Springer-Verlag 2009

Abstract Purpose To examine the pharmacokinetics of amikacin and its pharmacokinetic pharmacodynamic (PKPD) relationship in neonates. To develop an alternative dosing strategy for amikacin in neonates. Methods A population PKPD analysis was performed using data collected from 80 neonates with gestational ages from
C. M. T. Sherwin (*) Division of Clinical Pharmacology, Cincinnati Childrens Hospital Medical Center, 3333 Burnet Avenue, MLC 6018, Cincinnati, OH 45229-3039, USA e-mail: catherine.sherwin@cchmc.org D. M. Reith Department of Womens and Childrens Health, Dunedin School of Medicine, University of Otago, P.O. Box 913, Dunedin, New Zealand e-mail: david.reith@stonebow.otago.ac.nz S. Svahn University of Uppsala, Uppsala, Sweden e-mail: svahn.sofia@gmail.com A. Van Der Linden Department of Pathology, Dunedin School of Medicine, Dunedin, New Zealand e-mail: antje.vanderlinden@otagodhb.govt.nz R. S. Broadbent Department of Womens and Childrens Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand e-mail: roland.broadbent@otago.ac.nz N. J. Medlicott New Zealands National School of Pharmacy, University of Otago, Dunedin, New Zealand e-mail: natalie.medlicott@otago.ac.nz

24 to 41 weeks. The final pharmacokinetic model analysed 358 amikacin concentrations. All neonates were >72 hours postnatal age. Simulations were performed to develop a new dosing strategy. Results The final covariate model was clearance=0.23 (current weight/2)0.691 (postmenstrual age/40)3.23 and volume of distribution=0.957(current weight/2)0.89. Following the logistic regression analysis of treatment failure, new amikacin target concentrations were estimated and used in development of an alternative dosing strategy. Conclusion Simulation of a new dosing regimen yielded the following recommendations: 15 mg/kg at 36-h intervals, 14 mg/kg at 24-h intervals and 15 mg/kg at 24-h intervals for neonates 28 weeks, 2936 weeks and 37 weeks postmenstrual age respectively. Keywords Amikacin . Neonates . Population pharmacokinetics . Pharmacodynamics

Introduction Bacterial sepsis is common in neonates and particularly in preterm neonates because of their immature immune system [1]. Amikacin is a semi-synthetic derivative of kanamycin which has broad in vitro and in vivo activity against most aerobic Gram-negative bacteria and is effective against some strains of bacteria that are resistant to other aminoglycosides [2, 3]. Amikacin is indicated in the short-term treatment of serious infections caused by strains of Pseudomonas sp., E. coli, Klebsiella pneumoniae, Serratia sp. and Staphylococcus species [4]. Specifically in the neonatal population, amikacin is also used to treat lateonset sepsis caused by coagulase-negative Staphylococcus species. For Gram-negative sepsis, it is recommended that

706

Eur J Clin Pharmacol (2009) 65:705713

the amikacin peak serum concentration should be higher [maximum serum concentration (Cmax)/minimum inhibitory concentration (MIC) ratio greater than 8:1] in the first to second days of treatment [57]. However, these recommendations have not been based upon studies in neonates, for which there is a paucity of data with regard to amikacin pharmacokinetic-pharmacodynamic (PKPD) relationships. Several studies have demonstrated that conventional paediatric dosing regimens are not well adapted to neonates and result in inconsistent serum concentrations, particularly in extremely low-birth-weight neonates [5]. Peak concentrations are often lower than expected for optimal bactericidal effect, and trough concentrations are often too high to be considered safe [5, 8]. The concentrations related to toxicity in adults have been extrapolated to neonates, but there is little evidence indicating the specific toxic concentrations for amikacin in neonates [9]. Given the inconsistency in the literature and the limited evaluation of extended interval dosing with amikacin in neonates there is a need to design a dosing regimen adapted to extremely premature neonates. However, before a new dosing regimen can be developed, the pharmacokinetics (PK) of amikacin need to be further explored, in particular, the influence of covariates. The present study was undertaken to investigate the pharmacokinetics and pharmacodynamics of amikacin in neonates, and the influence of covariates upon these parameters. This information was used to develop an optimal dosing strategy for neonates.

culture-proven sepsis, sex, serum creatinine (mol/L), maximum C-reactive protein (CRP) (mg/L) during treatment, Apgar score at 1 min and Apgar score at 5 min. Post-menstrual age was calculated as gestational age plus post-natal age at birth in completed weeks. The standard NICU protocol for suspected sepsis required a blood culture, full blood count and CRP to be performed. Amikacin was discontinued after 48 h unless neonates were confirmed septic or remained clinically unwell. Neonates with culture-proven sepsis, positive microbial infection confirmed by cerebral spinal-fluid tap, clinical unresolved signs or a persistent maximum CRP > 40 mg/L were classified as septic. For those neonates with culture-proven sepsis, treatment failure (TF) was defined as a repeated infection caused by the same bacteria within 5 days and/or a treatment switch to another antimicrobial, usually vancomycin, due to no apparent clinical improvement with amikacin treatment. Amikacin therapy and sampling Amikacin was administered as an intravenous infusion over 30 min using a syringe driver piggybacked to a Baxter pump delivering a continuous IV infusion. This was followed with 1 mL normal (0.9%) saline given over 30 min. Amikacin dose in the first week after birth was based on current weight and gestational age. Neonates 27 and 2730 weeks gestational age received 18 mg/kg at 48- and 36-h intervals respectively. Neonates 31 to 33 weeks gestational age received 16 mg/kg at 36-h intervals. Neonates 34 weeks gestational age received 15 mg/kg at 24-h intervals. From 1 week of age, neonates were given an initial dose of 15 mg/kg and were then dosed based on gestational age as described above. Amikacin and creatinine assays Amikacin peak serum concentrations were measured 60 min after the start of the IV infusion, and trough concentrations were measured at 24 h. Amikacin concentrations were measured using a fluorescence polarisation immunoassay with an Abbott TDx kit (Abbott Park, IL). Serum creatinine levels were obtained within 24 h of amikacin levels and were assayed by the Jaffe alkaline picrate method (Roche Diagnostics, Indianapolis, IN). CRP was determined using a Roche Tinaquant, immunoturbidimetric method (Roche Diagnostics, Indianapolis, IN). Amikacin Etests (ABBiodisk, Solna, Sweden) were performed on the isolates of bacteria cultured from 26 septic neonates to determine amikacin MIC. Etests were not performed on streptococci or enterococci isolates, as these are intrinsically resistant. All analyses were carried out at the Otago Diagnostic Laboratory at Dunedin Hospital.

Methods Patients A retrospective chart review was performed that included all neonates treated with amikacin in the neonatal intensive care unit (NICU) at Dunedin Hospital from 1 October 2003 to 31 January 2007. Amikacin was commenced for treatment of suspected or culture-proven late-onset neonatal sepsis from 3 days post-natal age. As per the Dunedin Hospital NICU protocol, neonates <72 h post-natal age are treated with gentamicin and were not included in this study. Data were collected for 82 neonates who had at least one therapeutic amikacin concentration recorded. Two patients were excluded from the review due to incomplete data. Three amikacin concentrations were also excluded from the PK analysis, two due to intravenous leakage during administration and one was considered an outlier due to an unexplainable, exceptionally high concentration. The study protocol was reviewed by the Otago Ethics Committee and considered an audit. The data obtained from the review of medical charts included gestational age (weeks), post-natal age (days), birth weight (kg), current weight at treatment (kg), presence of

Eur J Clin Pharmacol (2009) 65:705713

707

Pharmacokinetic modelling The population PK analysis of amikacin used NONMEM version 5, release 1.1 (non-linear mixed effect modelling; GloboMax, Hanover, MD, USA). A mixed effects one-compartment, first-order elimination model was developed. The terms for variability in the model included between-subject variability (BSV), betweenoccasion variability (BOV) and residual variability. An omega block was used in the model to account for the high correlation between clearance and volume of distribution. Linear and power error models were explored and the random-effect error models included BSV, BOV and residual variability. The final BSV and BOV error models used an exponential error model. The residual (unexplained) variability was evaluated using a combined proportional (RUV-CV) and additive (RUVSD) error model. Plots were generated to screen for relationships between the estimates of the parameters from the base model and potential covariates. The independent variables (covariates) included gestational age (weeks), postnatal age (days), current weight, sepsis, serum creatinine, sex, Apgar scores and post-menstrual age. A further exploratory analysis of plots was also undertaken by plotting post-hoc eta predictions for clearance and volume of distribution against the biologically plausible covariates. For inclusion of covariates, an additive and multiplicative approach was used initially in a univariate analysis. A forward and backward stepwise regression method was used to determine the best covariate model. A statistically significant improvement in the fit of the model was based on minimisation of the objective function value (OFV) and hypothesis-testing using the 2 distribution. The final model was determined by investigating significant minimisation of the OFV and visual inspection of diagnostic plots. After identification of probable significant covariates, linear and power models were investigated. A power model was chosen as it provided a greater reduction in the OFV than linear models with the same number of model parameters. Bootstrap The final PK model was validated by using the bootstrap approach. The sampling strategy used a non-replacement technique [10]. A bootstrap was performed on the final refined covariate PK model, which was based on the whole population. The bootstrap repeatedly fitted the data to the final model and generated 1,000 replicates. The percentage of runs where the covariate effects were determined to be significant was calculated, and each model parameter was reported as median and 95% CI.

Pharmacodynamic analysis The pharmacodynamic (PD) analysis was undertaken using a logistic regression technique for making predictions when the dependent variable (Y) was dichotomous rather than continuous, and the independent variables were continuous or discrete. The outcome of Y allowed for only two possible values. These were represented by one, a success, and zero, a failure. The mean of the dichotomous random variable (p) was the proportion of times Y=1 or treatment was successful. The logistic function did not yield a value that was either negative or greater than one, and it was restricted to estimating the value of p to the required range. Modelling p with the logistic function was equivalent to fitting a linear regression model where the continuous outcome Y was replaced by the logarithm of the odds of success [11]. The PD analysis used treatment failure as the outcome variable and included all the neonates with culture-proven sepsis (n = 26). The logistic regression aimed to predict the odds ratios for patients with TF or those likely to meet the TF criteria based on the collected clinical data. The effect size of the exposure variables was expressed as odds ratio (95% CI). Relative risk was calculated to determine the risk of treatment failure occurring dependent on the amikacin therapeutic peak concentration and MIC. Simulation of current and proposed dosing regimens The final covariate PK model was used to simulate serum concentrations during the current dosing regimen. Then an alternative dosing regimen was explored using simulations with the same model. A nonparametric dataset of covariate distributions was used to represent 1,000 virtual patients using MATLAB (student version 7.1, The Mathworks, 2005). The covariates of interest were post-menstrual age (weeks) and current weight (kg), and these ranged from 24.7 to 44.1 and 0.45 to 4.43 respectively, based on a dataset that comprised 719 individual neonates. The simulation modelled an intravenous infusion of amikacin given over 30 min for two doses. The new dosing regimen was proposed to achieve treatment success as defined by Cmax in the range 2435 mg/L and area under the concentration-time curve over 24 h (AUC24) in the range 130590 mgh/L. An extended interval dosing regimen was developed in line with current literature recommendations for dosing aminoglycosides in neonates [8, 12, 13].

Results Eighty neonatal patients were included in the final study for which there were 358 amikacin peak and trough

708

Eur J Clin Pharmacol (2009) 65:705713

concentrations. In this population, there were 46 (57.5%) extremely premature neonates, with a gestational age of <28 weeks, and 44 (55%) of these neonates were extremely low-birth-weight infants (<1,000 g) (Table 1). There were 98 treatment episodes including 35 (35.7%) confirmed septic episodes from 26 (32.5%) neonates. Four neonates each received treatment for two separate episodes of culture-proven sepsis, and one patient had three treatment episodes for confirmed sepsis. All episodes of culture-proven sepsis were from blood cultures, with no confirmed episodes diagnosed from urine or cerebral spinal-fluid tap cultures. The clinical diagnoses included pneumonia (3), bacterial meningitis (2), congenital sepsis (3) and suspected necrotising enterocolitis (3). Seven neonates in the study population died, five within 1 week of birth, with four of those from overwhelming septicaemia. Twenty-one (21.4%) septic episodes in 12 individual patients met the predefined criteria for treatment failure. The majority of neonatal sepsis was caused by Staphylococcus epidermidis (14), non-specified Staphylococcus sp. (10) and Staphylococcus aureus (3). Remaining sepsis events were attributed to Staphylococcus hominis (2), Staphylococcus capitis (1), Staphylococcus warneri (1), E. coli (2), Enterococcus faecalis (1) and Enterococcus faecium (1). Five of the cultures contained mixed growth with bacterial species and/or fungal species being isolated. Forty-five amikacin E-tests were performed. Staphylococcus epidermidis amikacin MIC ranged from 1.5 to 12 mg/L and for non-specified Staphylococcus sp., MIC ranged from 0.75 to 3 mg/L. Only 26 isolates were confirmed as causative septic agents, 14 of which were from episodes of treatment failure. Pharmacokinetic model The base PK model estimated amikacin clearance as 0.069 L/h (0.486 SE %, 0.0590.078 95% CI) and volume of distribution as 0.63 L (3.42 SE %, 0.560.69 95% CI),

with BSV estimated at 24.4% (5.83 SE %) for CL and 4.52% (2.61 SE %) for V. For residual variability, the coefficient of variability (RUV-CV) was estimated at 13.7 (2.46 CV %) and standard deviation (RUV-SD) was 2.34 1.18 mg/L. The model was allowed to determine the allometric scale most appropriate for the current weight, resulting in a power function of 0.691 being used. Current weight had the most significant effect on the model. The final covariate model was chosen as it produced the most significant minimisation of OFV ( 330.4) and reduced the BSV and residual variability. Visual inspection of diagnostic plots was also used to confirm selection of the final covariate model (Fig. 1). The final covariate PK model is shown in equation 1. CL q1 CWT=2 q3 PMA=40 q4 L=h V q 2 CWT=2 q5 L 1

where CL refers to clearance, V to volume of distribution, CWT to current weight and PMA to post-menstrual age. The final PK covariate model estimates and results from the bootstrap model are outlined in Table 2. The final model accounted for some of the heterogeneity within the data as the predicted concentration vs. weighted residual plot illustrated (Fig. 2). Pharmacodynamic model There were 35 confirmed septic episodes from 26 neonates. Univariate analysis of the variables showed there was no influence from amikacin AUC, sex, post-natal age, amikacin peak or amikacin MIC upon treatment failure when included in the logistic regression model as independent variables. Other than amikacin peak/MIC ratio, there were no independent predictors of treatment failure (Table 3). In those with culture-proven sepsis, the relative risk (95% CI) for treatment failure was 2.86 (1.575.19) for amikacin peak/ MIC <6 and 2.25 (0.955.34) for amikacin peak/MIC <8.

Table 1 Demographic summary of the amikacin study population, presented as median (range) Characteristics of patients (n, %) Gestational age (weeks) Post-natal age (days) Post-menstrual age (weeks) Birth weight (kg) Current weight (kg) Male sex (n, %) Apgar score at 1 min Apgar score at 5 min Serum creatinine (mol/L) C-reactive protein maximum (mg/L) Septic (n=31, 38.75%) 27 (2434) 9 (364) 28.8 (24.741.1) 0.93 (0.582.1) 0.97 (0.633.51) 23 (74%) 7 (19) 9 (210) 58 (42111) 30 (0.5239) Non-septic (n=49, 61.25%) 28 (2441) 9 (331) 30.0 (24.744.0) 1.02 (0.44.4) 1.20 (0.454.43) 23 (46%) 7 (19) 10 (510) 59 (20111) 1 (0.576) All (n=80, 100%) 28 (2441) 9 (364) 29.43 (24.744.0) 0.97 (0.444.4) 1.03 (0.454.43) 46 (57%) 7 (19) 9 (210) 58.5 (20111) 2 (0.5239)

Eur J Clin Pharmacol (2009) 65:705713

709

5 3 1 -1 -3 -5 25 28 31 34 37 40 43

5 3 1 -1 -3 -5 0 8 16 24 32 40 48

WRES

WRES

56

64

72

80

88

PMA (weeks)

PNA (days)

a) WRES vs. PMA base model

5 3 5 3 1 -1 -3 -5 25 28 31 34 37 40 43 0 8 16

b) WRES vs. PNA base model

WRES

-1 -3 -5

WRES

24 32

40 48

56

64 72

80

88

PMA (weeks)

PNA (days)

c) WRES vs. PMA final model

d) WRES vs. PNA final model

Fig. 1 Diagnostic plots comparing the base and final models. WRES Weighted residual, PMA post-menstrual age, PNA post-natal age

Simulations of dosing regimens The existing amikacin dosing regimen recommended target concentrations for peaks between 20 and 30 mg/L with a
Table 2 NONMEM estimates of population pharmacokinetic parameters Parameter Final model Estimates Clearance (L/h) CWT (3) PMA (4) Volume of distribution (L) CWT (5) BSV-CL (%) BSV-V (%) RUV-CV (%) RUV-SD (%) 0.23 0.691 3.23 0.957 0.89 4.6 0.446 3.8 2.42

trough concentration below 5 mg/L. The present study revised the target concentrations using the results of the PD analysis. The optimum target for Cmax was adjusted from a peak of 2030 mg/L to 2435 mg/L (which was considered,

Bootstrap (n=1,000) 95% CI 0.173 to 0.287 0.307 to 1.08 1.82 to 4.64 0.883 to 1.03 0.783 to 0.997 0.457 to 9.66 0.181 to 1.07 1.88 to 5.72 0.44 to 4.4 Median 0.23 0.687 3.23 0.965 0.9 4.5 0.477 4.0 2.09 95% CI 0.173 to 0.306 0.073 to 0.972 1.805 to 4.955 0.8725 to 1.03 0.76 to 0.98 0.209 to 9.675 0.03 to 1.015 1.68 to 6.44 0.56 to 3.88

CWT Current weight, PMA post-menstrual age, 95% CI confidence interval calculated from parameter standard errors, V volume of distribution, CL clearance, BSV-CL between-subject variability related to clearance, BSV-V between-subject variability related to volume of distribution, RUVCV coefficient of variation of residual error (proportional error), RUV-SD coefficient of variation of residual error (additive error)

710
56

Eur J Clin Pharmacol (2009) 65:705713

49 42 35 28 21 14 7 0 0 7 14 21 28 35 42 49 56

Observed concentrations (mg/L)

a)
5

DV vs. PRED final model

because of the potential for toxicity, to be an acceptable upper limit) [4, 6]. The upper and lower bounds for AUC24 were 130 and 590 mgh/L, which were taken from the range obtained by the univariate logistic regression for treatment failure. The bounds for weight were 0.46.0 kg, and postmenstrual age was adjusted to fit the required categories. Table 4 outlines an example of percentage of success achieved with simulated amikacin dosing for neonates with a post-menstrual age 2327 weeks. A dosing regimen with a dose range of 1415 mg/kg and dosing interval of 24 36 h based on post-menstrual age resulted in a high rate of success for both AUC24 and Cmax on days 1 and 2 (Table 5). Using this regimen, a serum amikacin concentration test could be performed at 24 h post-dose in order to detect potential toxicity, for example using a criteria of trough concentration <2 mg/L. If necessary, the dosing interval could then be increased in the presence of unacceptably high amikacin levels at 24 h post-dose.

Predicted concentrations (mg/L)

WRES

Discussion
1

-1

-3

-5 0 9 18 27 36 45 54

Predicted concentrations (mg/L)

b)

WRES vs. PRED final model

5 3

1 -1 -3 -5

0.0

3.2

6.4

9.6

12.8 16.0 19.2 22.4 25.6 28.8 32.0

Time (hours) post dose

c)

WRES vs. time (hours) final model

Fig. 2 Pharmacokinetic model: diagnostic plots for final covariate model. DV Dependent variable, PRED predicted concentration, WRES weighted residual

The principal findings of the present study were that the main determinants of amikacin clearance were current weight and post-menstrual age, the main determinant of volume of distribution was current weight and the main predictor of TF was peak/MIC ratio <8. Although the PK findings are similar to those previously reported, the present study offers an extension of the PK modelling with application of PD data in the simulation of a new dosing regimen. Overall, few population PK studies have been conducted to describe the PK of amikacin in neonates [1416]. Published data on the use of amikacin are even more limited for neonates with birth weights below 1.5 kg and gestational age <30 weeks [17]. The BSV and residual variability reported in the present study are lower than those reported in previous studies [18]. The present study included more extremely premature neonates (gestational age <28 weeks, 57.5%) and extremely low-birth-weight infants (<1000 g, 55%) than previously published studies investigating amikacin PK in neonates. Consideration was given to investigating the potential effect of shrinkage on the empirical Bayes estimates [19], but this was not considered to explain the lower observed variability determined in the final model of this study. There is a wide BSV in relation to the PK of amikacin [5], and this makes it difficult to achieve a safe and effective dosing regimen particularly for extremely preterm neonates [20, 21]. Differences in body composition and the renal immaturity associated with neonates contribute to the variability of the PK parameters, particularly clearance [20]. Other variables that have been reported to influence

WRES

Eur J Clin Pharmacol (2009) 65:705713 Table 3 Univariate logistic regression for treatment failure Exposure variable MIC Amikacin peak concentration Current weight (kg) C-reactive protein maximum (mg/L) AUC (mgh/L) Male sex Post-menstrual age (weeks) Amikacin peak concentration and MIC Cmax and MIC Amikacin peak/MIC <6 Amikacin peak/MIC <8 Number 25 31 35 35 35 35 35 22 24 22 22 Median (range) or n (%) 3 (012) 27.7 (17.136.8) 1.0 (0.633.51) 57 (0.5239) 267.49 (133.39589.62) 21 male (60) 29.57 (2541.14) 10.8 (2.371.6) 9.2 (1.9162.9) 2 (9%) 4 (18%) OR (95% CI) 1.30 0.88 1.35 1.01 1.01 0.42 0.97 1.02 1.01 2.86 2.25

711

OR Odds ratio, AUC area under the concentration-time curve,, Cmax maximum peak concentration, MIC minimum inhibitory concentration
a

Values are relative risk instead of odds ratio (as predicts success perfectly)

(0.851.98) (0.741.04) (0.404.50) (0.961.07) (1.001.01) (0.101.80) (0.781.21) (0.961.08) (0.981.05) (1.575.19)a (0.955.34)a

variability include renal function, gestational age, post-natal age, haematocrit, fever and lean body weight [3]. The present study showed post-menstrual age to have the greatest significant effect on clearance. Post-menstrual age is suggested to be a predictor of amikacin clearance because it predicts the time course of development of glomerular filtration rate (GFR) [22]. GFR matures during infancy and approaches an adult rate (6 L/h per 70 kg) by 6 months post-natal age [23]. Post-natal age and gestational age were investigated as separate covariates in the PK model during

development but did not provide the best minimisation to the OFV. The study did not include neonates <72 h postnatal age as they were not treated with amikacin. As the present study only included neonates of more than 72 h of age, the rapid changes associated with renal function in neonates <72 h were not applicable to the model. The effects of gestational age and post-natal age when included as covariates in models are reported to provide disproportionate effects, and use of them as separate covariates may not be informative for renal clearance in

Table 4 Example of percentage of success achieved with simulated amikacin dosing for PMA 2327 weeks Run PMA (weeks) Dose (mg/kg) Interval (h) AUC24 success % day 1 99 99 99 99 97 94 91 99 99 99 99 99 99 99 99 99 99 99 99 AUC24 success % day 2 99 99 99 99 98 95 92 99 99 99 99 99 99 99 91 95 97 99 99 Cmax success % day 1 24 80 94 99 98 84 47 48 76 93 98 98 83 50 93 99 97 88 52 Cmax success % day 2 9 53 81 96 99 97 75 10 30 61 85 96a 98 90 17 44 72 93 97

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327 2327

19 18 17 16 15 14 13 19 18 17 16 15 14 13 17 16 15 14 13

48 48 48 48 48 48 48 36 36 36 36 36 36 36 24 24 24 24 24

AUC24 Area under the concentration-time curve for 24 h, Cmax maximum peak concentration
a

Highest percentage success without the expense of prolonging dosing interval

712 Table 5 Proposed dosing regimen based on achieving optimal AUC24 and Cmax PMA (weeks) 28 2932 3336 37 Dose (mg/kg) Interval (h) AUC24 success % day 1 99 99 97 78 AUC24 success % day 2 99 99 97 76

Eur J Clin Pharmacol (2009) 65:705713

Cmax success % day 1 98 96 99 95

Cmax success % day 2 97 97 98 93

15 14 14 15

36 24 24 24

Note: Dosing may be modified by measuring serum amikacin concentration at 24 h post-dose. Dosing regimen does not apply to neonates of <72 h post-natal age PMA Post-menstrual age, AUC24 area under the concentration-time curve for 24 h, Cmax maximum peak concentration

neonates >72 h age. This is stated to be particularly evident beyond the initial neonatal period, and therefore it may be more appropriate to use post-menstrual age [21, 24]. The PK base model in the present study estimated clearance of 0.069 L/h (1.15 mL/min) in neonates with a gestational age of 2441 weeks. Published PK models have previously reported amikacin clearance as 0.75 and 0.87 mL kg1 min1 in neonates of less than 31 weeks gestation [8, 25]. In neonates less than 72 h old, with the majority comedicated with non-steroidal anti-inflammatory drugs, amikacin clearance has been reported as reduced, at 0.60 mL kg1 min1 for gestational age 2830 weeks and 0.44 mL kg1 min1 for gestational age <28 weeks [23, 25]. The primary determinant of amikacin volume of distribution in the present study was current weight. Previous studies found the covariates influencing V in neonates to be sepsis, body water and post-natal age [14, 26]. Patients with severe sepsis may have substantial changes in the extracellular fluid volume which may alter the volume of distribution of many drugs [27]. Based on their relative higher water content, preterm neonates already have a higher volume of distribution for hydrophilic drugs. Therefore, a relatively higher dose per kilogram of amikacin is deemed necessary in more-preterm neonates to achieve a sufficient concentration at the site of infection [20]. Although previous studies report substantial changes in volume of distribution during the first weeks of life, the present study included only neonates more than 72 h of age and hence might not have detected these changes [5, 8, 21, 25, 28]. An increase in volume of distribution associated with gestational age is suggested to be related to an increase in lean body mass particularly around 36 weeks gestational age rather than an increase in fat body mass. In neonates, anatomical and functional immaturity of the kidney limits glomerular and tubular functional capacity. Renal maturation has been shown to be related to gestational age [29]. Changes in GFR in neonates are related to nephrogenesis, which is not complete until around 34 weeks gestational age [30]. Incomplete nephrogenesis means that premature

neonates cannot respond to haemodynamic adjustments as effectively as full-term neonates [31]. This suggests that amikacin dosage regimens should be individualised especially in the 34- to 38-week gestational age group [5] by adjusting the dose according to body weight and the dosing interval according to both body weight and post-menstrual age. Results from the present study indicated the prime determinant of treatment failure was a peak/MIC <8. The ability to achieve a therapeutic maximum serum concentration (Cmax) can be critical to patient survival because of a significant decrease in the rate of mortality due to infection in critically ill patients [3, 21, 3234]. Hence, extendedinterval dosing regimens are recommended as they are expected to result in higher Cmax and greater efficacy [5, 8, 13, 20, 21, 23, 33]. However, there is also a risk that extending the dosage interval beyond 24 h might provide an opportunity for bacterial re-growth. There were various limitations associated with the present study and this was reflected in the results of the PK model, PD models, the simulations and the proposed dosing regimens for amikacin in this neonatal population. There were a limited number of neonates used for the PK and PD analyses. However, numbers will always be limited in any prospective observational study that identifies adverse outcomes (e.g. treatment failure) because once a problem is identified clinicians will take immediate corrective action. In addition, the dataset consisted of 55% extremely low-birth-weight infants (< 1,000 g) and 57.5% extremely premature neonates (gestational age <28 week), providing a possible bias in the PK model. The number of older neonates was limited as the population dataset contained only 10 (12.5%) neonates with gestational age 34 weeks.
Acknowledgements The authors would like to acknowledge Professor Stephen Duffull, School of Pharmacy, University of Otago, Dunedin, New Zealand, for his assistance with the PK modelling and the simulations. Catherine Sherwin is supported by a Freemasons Postgraduate Fellowship in Paediatrics and Child Health from the Freemasons of New Zealand.

Eur J Clin Pharmacol (2009) 65:705713

713 18. Berger A, Kretzer V, Gludovatz P, Heinze G, Haiden N, Pollak A (2004) Evaluation of an amikacin loading dose for nosocomial infections in very low birthweight infants. Acta Paediatrica 93:356360 19. Savic RM, Karlsson MO (2007) Importance of shrinkage in empirical bayes estimates for diagnostics and estimation: problems and solutions. Abstracts of the Annual Meeting of the Population Approach Group in Europe, p. 16 20. Allegaert K, Cossey V, Langhendries JP, Naulaers G, Vanhole C, Devlieger H, Van Overmeire B (2004) Effects of coadministration of ibuprofen-lysine on the pharmacokinetics of amikacin in preterm infants during the first days of life. Biol Neonate 86:207211 21. Treluyer JM, Merle Y, Tonnelier S, Rey E, Pons G (2002) Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children. Antimicrob Agents Chemother 46:13811387 22. Koren G, James A, Perlman M (1985) Simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn. Clin Pharmacol Ther 38:680685 23. Allegaert K, Anderson BJ, Cossey V, Holford NHG (2005) Limited predictability of amikacin clearance in extreme premature neonates at birth. Br J Clin Pharmacol 61:3948 24. Bueva A, Guignard JP (1994) Renal function in preterm neonates. Pediatr Res 36:572577 25. Kenyon CF, Knoppert DC, Lee SK, Vandenberghe HM, Chance GW (1990) Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. Antimicrob Agents Chemother 34:265268 26. Lingvall M, Reith DM, Broadbent R (2005) The effect of sepsis upon gentamicin pharmacokinetics in neonates. Br J Clin Pharmacol 59:5461 27. Mann HJ, Fuhs DW, Awang R, Ndemo FA, Cerra FB (1987) Altered aminoglycoside pharmacokinetics in critically ill patients with sepsis. Clin Pharm 6:148153 28. Padovani EM, Pistolesi C, Fanos V, Messori A, Martini N (1993) Pharmacokinetics of amikacin in neonates. Dev Pharmacol Ther 20:167173 29. Besunder JB, Reed MD, Blumer JL (1988) Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (part ii). Clin Pharmacokinet 14:261286 30. van den Anker JN (1996) Pharmacokinetics and renal function in preterm infants. Acta Paediatr 85:13931399 31. Aperia A, Broberger O, Elinder G, Herin P, Zetterstrom R (1981) Postnatal development of renal function in pre-term and full-term infants. Acta Paediatr Scand 70:183187 32. Moore RD, Smith CR, Lietman PS (1984) Association of aminoglycosides plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med 77:657662 33. Moore RD, Lietman PS, Smith CR (1987) Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 155:9399 34. Noone P, Parsons TM, Pattison JR, Slack RC, Garfield-Davies D, Hughes K (1974) Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis. Br Med J 1:477481

References
1. Clapp DW (2006) Developmental regulation of the immune system. Semin Perinatol 30:6972 2. Petersen PO, Wells TG, Kearns GL (1991) Amikacin dosing in neonates: evaluation of a dosing chart based on population pharmacokinetic data. Dev Pharmacol Ther 16:203211 3. Zaske DE, Strate RG, Kohls PR (1991) Amikacin pharmacokineticswide interpatient variation in 98 patients. J Clin Pharmacol 31:158163 4. Bristol-Meyers S (2001) Amikin. Bristol-Myers Squibb Pharmaceuticals, Noble Park, Australia 5. Bleyzac N, Varnier V, Labaune JM, Corvaisier S, Maire P, Jelliffe RW, Putet G, Aulagner G (2001) Population pharmacokinetics of amikacin at birth and interindividual variability in renal maturation. Eur J Clin Pharmacol 57:499504 6. Young TE, Mangum B (2002) Neofax, 15 ed. Acorn Publishing, Raleigh 7. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:112 8. Langhendries JP, Battisti O, Bertrand JM, Francois A, Kalenga M, Darimont J, Scalais E, Wallemacq P (1998) Adaptation in neonatology of the once-daily concept of aminoglycoside administration: evaluation of a dosing chart for amikacin in an intensive care unit. Biol Neonate 74:351362 9. Cookson B, Tripp J, Leung T, Williams JD (1980) Evaluation of amikacin dosage regimes in the low and very low birthweight newborn. Infection 8(Suppl 3):239242 10. Ette EL, Williams PJ, Kim YH, Lane JR, Liu MJ, Capparelli EV (2003) Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol 43:610623 11. Pagano M, Gauvreau K (1993) Principles of biostatistics. Wadsworth Publishing, Belmont, CA 12. Kotze A, Bartel PR, Sommers DK (1999) Once versus twice daily amikacin in neonates: prospective study on toxicity. J Paediatr Child Health 35:283286 13. Langhendries JP, Battisti O, Bertrand JM, Francois A, Darimont J, Ibrahim S, Tulkens PM, Bernard A, Buchet JP, Scalais E (1993) Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Dev Pharmacol Ther 20:220 230 14. Botha FJH, van der Bijl P, Seifart HI, Parkin DP (1996) Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient. Intensive Care Med 22:443446 15. Assael BM, Parini R, Rusconi F, Cavanna G (1982) Influence of intrauterine maturation on the pharmacokinetics of amikacin in the neonatal period. Pediatr Res 16:810815 16. Botha JH, du Preez M, Miller R, Adhikari M (1998) Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models. Eur J Clin Pharmacol 53:337341 17. Kenyon CF, Knoppert DC, Lee SK, Vandenberghe HM, Chance GW (1990) Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. Antimicrob Agents Chemother 34:265268