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<p>ORIGINAL ARTICLE</p><p>Pharmacokinetics of once-daily arnikacin</p><p>in pediatric patients</p><p>Laurence Belfayol', Philippe Talon2, Matthieu Eveillardl, Patrice Alet'</p><p>and Francise Fauvelle'</p><p>'Laboratoire de Pharmacie Clinique and 2Service de Pkdiatrie, Montfermeil, France</p><p>Objective: To study the pharmacokinetic parameters of a once-daily regimen of amikacin (15 mg/kg) in association with</p><p>other antimicrobial agents in 35 children with severe Gram-negative infections.</p><p>Methods: A Bayesian approach was developed to optimize the amikacin regimen. The predictive performance was</p><p>assessed by computing bias and precision. Each patient was evaluated for toxicity after 5 days of treatment.</p><p>Results: Peak amikacin concentrations on days 2 and 5 of therapy averaged 31.3 * 9.0 mg/L and 32.4 * 7.4 mg/L,</p><p>respectively. To achieve peak serum concentrations between 30 and 40 mg/L, individualized dosage was necessary in</p><p>19 of 35 children. The pharmacokinetic parameters showed large interindividual variations, with a mean half-life of 2 h</p><p>and a mean volume of distribution of 0.36 Ukg. No nephrotoxicity was observed in any of the children. After</p><p>individualization of dosage on the basis of one measurement of peak concentration, no significant differences were</p><p>observed between predicted and subsequently measured amikacin concentrations.</p><p>Conclusions: Once-daily dosage of arnikacin (15 mg/kg) is well tolerated in pediatric patients; however, a loading dose</p><p>of 20 mg/kg is recommended to achieve a therapeutic peak value between 30 and 40 mg/L. Initial serum monitoring is</p><p>essential in a population such as children, with wide interpatient variability. Using the Bayesian approach, the amikacin</p><p>regimen in children can then be predicted with minimal bias and good precision.</p><p>Keywords: Amikacin, pediatric patients, pharmacokinetics, drug monitoring</p><p>INTRODUCTION</p><p>Aminoglycoside antibiotics are very important, in</p><p>association with other antimicrobial agents, in the</p><p>treatment of Gram-negative infections. A daily regimen</p><p>administered in a single dose has been effective in</p><p>several studies. Once-daily regimens of amikacin [l],</p><p>netilmicin [2] or gentamicin [3] are less toxic than, and</p><p>equally efficient as, more frequent administration. The</p><p>volume of distribution is inversely correlated with age</p><p>[4] and is greater in children than in adults [5]. This</p><p>interpatient variation in volume of distribution has a</p><p>direct effect on the therapeutic peak levels achieved [6].</p><p>Because of this wide variation in pharmacokinetic</p><p>parameters and the low therapeutic index, amino-</p><p>glycosides are drugs that require an individualized</p><p>dosage. A Bayesian forecasting program has been</p><p>described to adjust the aminoglycoside dosage [7-lo].</p><p>The Bayesian method is a good approach in pehatric</p><p>patients, because few serum samples per patient are</p><p>required to estimate the pharmacokinetic parameters</p><p>for optimizing dosage regimens. The pharmacokinetics</p><p>of amikacin have been documented in critically 111 [ll]</p><p>and neutropenic children [12]. While the serum</p><p>concentrations and the clinical efficacy of amikacin</p><p>have been studied in children with severe Gram-</p><p>negative infections [13,14], no information has been</p><p>reported on amikacin pharmacokinetics in these</p><p>patients. Therefore, the aim of this study was to</p><p>investigate the pharmacokinetics (in terms of dosage,</p><p>concentrations achieved and pharmacokmetic para-</p><p>meters) and to evaluate the toxicity of a once-daily</p><p>amikacin regimen (15 mg/kg per day) in pediatric</p><p>patients, as well as the Bayesian forecasting method for</p><p>predicting serum amikacin concentrations.</p><p>Corresponding author and reprint requests:</p><p>L. Belfayol, CHI Montfermeil, Service Pharmacie, 10 rue du</p><p>General Leclerc, 93370 Montfermeil, France</p><p>Tel: (33) 1 41 70 82 26 Fax: (33) 1 41 70 82 82</p><p>Accepted 22 April 1996</p><p>MATERIALS AND METHODS</p><p>Patient selection</p><p>Thirty-five children, ranging in age from 1 to 15 years,</p><p>who were receiving amikacin for serious infection or</p><p>186</p><p>B e l f a y o l e t al : P h a r m a c o k i n e t i c s o f a m i k a c i n in p e d i a t r i c p a t i e n t s 187</p><p>presumed infection, were included in the study. Severe</p><p>infections were defined as follows: pyelonephritis</p><p>(n= 12), pulmonary infection (n=4), meningitis (n=5),</p><p>febrile syndrome in AIDS (n = 2), bacteraemia (n = l ) ,</p><p>arthritis (n = 3), other locahzed infections (n = 8).</p><p>Twenty-two bacterial isolates were identified as respons-</p><p>ible: Escherichia coli(n = lo), Aeudomonus aeruginosa (n =2),</p><p>Proteus mirabilis (n = l) , Staphylococcus spp. (n = 4), Neisseria</p><p>meningitidis (n = 3), Haemophibs inzuenzae (n = 2).</p><p>Drug administration and dosage</p><p>Each patient received 15 mg/kg amikacin therapy at</p><p>doses ranging &om 100 to 750 mg as a 30-min intra-</p><p>venous infusion in 0.9% sodium chloride. Amikacin</p><p>was given to all patients in once-daily doses combined</p><p>with one or more other antimicrobial agents. The other</p><p>drugs co-administered were ceftriaxone (n = 22), cefo-</p><p>taxime (n = 7), ciprofloxacin (n = l), amoxycillin (n =</p><p>3) , oxacillin (n = l), teicoplanin (n = 1) and fosfomycin</p><p>(n = 3). For inclusion, all patients had to receive</p><p>amikacin for a minimum of 5 days. Venous blood</p><p>samples were collected from an indwelling catheter in</p><p>the non-infused forearm just before infusion (trough)</p><p>and 30 min after the end of infusion (peak). Blood</p><p>samples for follow-up peak and trough amikacin</p><p>concentrations were obtained at days 2 and 5. On day</p><p>2, the amikacin dosage was adjusted to achieve a peak</p><p>level of 230 mg/L and a trough level < 5 mg/L. On</p><p>day 5, peak and trough samples were collected, to</p><p>ensure that the actual levels in the serum were in fact</p><p>close to the calculated levels. Two pairs of peak and</p><p>trough values were required for each patient for</p><p>inclusion in the study. Serum concentrations of</p><p>amikacin were determined by a fluorescence polariza-</p><p>tion immunoassay (TDx, Abbott Diagnostic Division,</p><p>Rungis, France). The sensitivity of the assay was 0.8</p><p>mg/L. Replicate measurements (n = 5 ) of representa-</p><p>tive samples with concentrations in the region of 5, 10,</p><p>20 and 35 mg/L were made in order to determine the</p><p>mean and the standard deviation of each sample. The</p><p>error pattern of the TDx assay for amikacin is shown</p><p>in Figure 1. The resulting polynomial equation found</p><p>for this assay is:</p><p>SD (mg/L) = 0.000758C2 - 0.013354C</p><p>+ 0.097500</p><p>where SD represents the standard deviation of the</p><p>measurement and C represents the measured serum</p><p>concentration.</p><p>Evaluation of nephrotoxicity</p><p>The criterion of toxicity was an increase in serum</p><p>creatinine of 15% or more between days 2 and 5 of the</p><p>amikacin therapy.</p><p>0 5 1 0 1 5 2 0 2 5 3 0 3 5</p><p>Serum amikacin (rngh)</p><p>Figure 1</p><p>SD = standard deviation (mg/L).</p><p>Assay error pattern of the TDx assay for amikacin.</p><p>Bayesian forecasting of dosage</p><p>The pharmacokinetics of amikacin were described by a</p><p>one-compartment open model. Individual pharmaco-</p><p>kinetic parameters were calculated according to the</p><p>maximum Bayesian analysis a posteriori (Abbott PKS,</p><p>Abbott Diagnostic Division, Rungis, France). The data</p><p>required included age, gender, height, weight, serum</p><p>creatinine, amikacin dose, dosage interval and measured</p><p>serum concentrations. The initial population parameters</p><p>in this model were as follows: volume of distribution</p><p>( V d ) = 0.31 L/kg; non-renal clearance (CINR) =</p><p>0.0417 ml/min per kg; slope of the line between</p><p>amikacin clearance (C~T) and creatinine clearance</p><p>(CIcreat) = 0.815. Total clearance is calculated by the</p><p>following equation: C~T = C~NR + (slopex Clcre,,). The</p><p>coefficients of variation were set at 30% for Vd at 25%</p><p>for C ~ N R and at 40% for the slope. Creatinine clearance</p><p>was estimated by the method of Schwartz et al. [15].</p><p>Predictive analysis</p><p>The predictive performance was evaluated by the</p><p>methods described by Sheiner and Beal [16]. The pre-</p><p>dicted amikacin serum concentrations were compared</p><p>with those measured. Bias and precision were assessed,</p><p>respectively, by mean prediction error (ME) with 95%</p><p>confidence interval and root mean squared error</p><p>(RMSE) with the corresponding equations:</p><p>188 C l in ica l M i c r o b i o l o g y a n d In fec t ion . Vo lume 2 N u m b e r 3 , D e c e m b e r 1996</p><p>where C,,, and C,,l,,, represent the predicted and</p><p>measured concentrations. The bias was considered</p><p>significantly different if the 95% confidence interval d d</p><p>not include zero. A paired t-test between predicted and</p><p>measured concentrations was used to evaluate their</p><p>differences. A p-value < 0.05 was considered statistic-</p><p>ally significant.</p><p>RESULTS</p><p>The demographic parameters of indvidual children,</p><p>and the amikacin pharmacohnetic parameters are listed</p><p>in Table 1. The half-life of amikacin ranged from 1.1</p><p>to 4.4 h. The distribution volume of amikacin varied</p><p>widely from patient to patient. The mean peak and</p><p>trough amikacin serum concentrations on days 2 and 5</p><p>are shown in Table 2. The measured serum concentra-</p><p>tions showed large interindividual variations. O n day 2,</p><p>100% of the chddren had trough levels < 5 mg/L, 54%</p><p>of which were below the limit of detection of the assay.</p><p>O n day 5, two children had a trough level > 5 mg/L</p><p>(6.1 and 8.1 mg/L). To achieve therapeutic concentra-</p><p>tions between 30 and 40 mg/L, individual dosage was</p><p>necessary in 19 of 35 children. The dose required was</p><p>higher than the recommended dose of 15 mg/kg, with</p><p>a mean of 21 mg/kg. Measured and predicted serum</p><p>amikacin concentrations at both peak (n = 35) and</p><p>trough (n = 35) were compared in all patients &om</p><p>whom samples were available on day 5. The bias and</p><p>precision of Bayesian predictive performance are shown</p><p>Table 1 Characteristics of the chddren and pharmacokinetic data</p><p>1</p><p>2</p><p>3</p><p>4</p><p>5</p><p>6</p><p>7</p><p>8</p><p>9</p><p>10</p><p>11</p><p>12</p><p>13</p><p>14</p><p>15</p><p>16</p><p>17</p><p>18</p><p>19</p><p>20</p><p>21</p><p>22</p><p>23</p><p>24</p><p>25</p><p>26</p><p>27</p><p>28</p><p>29</p><p>30</p><p>31</p><p>32</p><p>33</p><p>34</p><p>35</p><p>Mean</p><p>ISD</p><p>F</p><p>F</p><p>M</p><p>F</p><p>M</p><p>M</p><p>M</p><p>M</p><p>M</p><p>F</p><p>F</p><p>F</p><p>F</p><p>M</p><p>F</p><p>M</p><p>M</p><p>F</p><p>F</p><p>M</p><p>M</p><p>M</p><p>F</p><p>F</p><p>M</p><p>F</p><p>F</p><p>M</p><p>M</p><p>M</p><p>M</p><p>M</p><p>M</p><p>M</p><p>M</p><p>10</p><p>9.5</p><p>2.5</p><p>1</p><p>10</p><p>5</p><p>8</p><p>9</p><p>1</p><p>2</p><p>9</p><p>5</p><p>4</p><p>14</p><p>10</p><p>4.5</p><p>13</p><p>3</p><p>4.8</p><p>1</p><p>10</p><p>7</p><p>1</p><p>9</p><p>4</p><p>10</p><p>8</p><p>2</p><p>1s</p><p>6</p><p>4.5</p><p>12</p><p>11</p><p>13</p><p>5</p><p>7.0</p><p>k4.3</p><p>23</p><p>33</p><p>13</p><p>26</p><p>20</p><p>19</p><p>25</p><p>14</p><p>22</p><p>20</p><p>16.8</p><p>60</p><p>38.5</p><p>17</p><p>23</p><p>11</p><p>18</p><p>9</p><p>35</p><p>18</p><p>10.1</p><p>45</p><p>16</p><p>34</p><p>23</p><p>15</p><p>40</p><p>18</p><p>14</p><p>40</p><p>34</p><p>49</p><p>20</p><p>9.9</p><p>9.2</p><p>23.5</p><p>f12.4</p><p>126</p><p>137</p><p>85</p><p>73</p><p>130</p><p>115</p><p>125</p><p>127</p><p>76</p><p>88</p><p>120</p><p>112</p><p>104</p><p>153</p><p>141</p><p>109</p><p>130</p><p>95</p><p>110</p><p>73</p><p>140</p><p>113</p><p>140</p><p>100</p><p>140</p><p>108</p><p>91</p><p>150</p><p>111</p><p>103</p><p>150</p><p>160</p><p>140</p><p>115</p><p>72.5</p><p>114</p><p>I 2 5</p><p>0.24</p><p>0.32</p><p>0.24</p><p>0.53</p><p>0.52</p><p>0.44</p><p>0.42</p><p>0.31</p><p>0.48</p><p>0.30</p><p>0.22</p><p>0.41</p><p>0.35</p><p>0.19</p><p>0.26</p><p>0.37</p><p>0.35</p><p>0.48</p><p>0.45</p><p>0.33</p><p>0.38</p><p>0.42</p><p>0.46</p><p>0.33</p><p>0.32</p><p>0.26</p><p>0.42</p><p>0.30</p><p>0.43</p><p>0.34</p><p>0.43</p><p>0.34</p><p>0.35</p><p>0.27</p><p>0.44</p><p>0.36</p><p>ko.08</p><p>1.1</p><p>1.8</p><p>1.3</p><p>1.9</p><p>2.2</p><p>2.2</p><p>1.6</p><p>1.5</p><p>3.9</p><p>0.9</p><p>1.7</p><p>1.9</p><p>1.6</p><p>1.1</p><p>2.1</p><p>1.3</p><p>2.8</p><p>1.3</p><p>2.8</p><p>1.3</p><p>4.1</p><p>1.8</p><p>4.4</p><p>1.8</p><p>1.5</p><p>1.9</p><p>3.9</p><p>1.1</p><p>1.3</p><p>1.4</p><p>1.6</p><p>1.4</p><p>3.5</p><p>1.2</p><p>4.0</p><p>2.0</p><p>kl.O</p><p>58.3</p><p>62.7</p><p>27.3</p><p>30.3</p><p>71.2</p><p>47.3</p><p>58.5</p><p>58.7</p><p>13.3</p><p>68.3</p><p>36.5</p><p>48.7</p><p>41.2</p><p>57.2</p><p>54.2</p><p>64.3</p><p>46.8</p><p>34.3</p><p>25.5</p><p>37.5</p><p>48.0</p><p>11.2</p><p>93.8</p><p>38.0</p><p>54.3</p><p>28.5</p><p>50.0</p><p>148.8</p><p>50.5</p><p>43.2</p><p>144.3</p><p>39.3</p><p>130.5</p><p>25.5</p><p>123</p><p>56.3</p><p>k33.8</p><p>T1,2 = half-life; KI = volume of distribution; C/T = total clearance</p><p>Bel fayo l e t al: Pharmacok inet ics of a m i k a c i n in p e d i a t r i c p a t i e n t s 189</p><p>Table 2</p><p>concentrations (mg/L)</p><p>Mean 5 SD trough and peak amikacin</p><p>Day 2 Day 5</p><p>Trough (n = 35) 1.1 ? 0.5 1.4 I 1.6</p><p>Peak ( n = 35) 31.3 5 9.0 32.4 1 7 . 4</p><p>(17.1-49.6) (17.3-50.0)</p><p>(0.8-2.4) (0.8-8.9)</p><p>in Table 3. For both peak and trough levels, the bias is</p><p>not significant ( p > 0.05). Among the mean measured</p><p>serum concentrations, the precision is greater for the</p><p>peak (+7.06 mg/L for 32.4 2 7.4 mg/L) than for the</p><p>trough (+1.70 mg/L for 1.4 & 1.6 mg/L). No sig-</p><p>nificant differences were observed between measured</p><p>and predicted trough (respectively, 1.4 4 1.6 mg/L</p><p>and 1.2 4 0.8 mg/L) and peak (respectively, 32.4 -t 7.4</p><p>mg/L and 33.3 & 5.4 mg/L). These data indicate that</p><p>serum amikacin concentrations in children can be</p><p>predicted with minimal bias and reliable precision. The</p><p>mean length of therapy was 6 days. Nephrotoxicity</p><p>could be evaluated in all children. No statistically</p><p>significant difference was found in serum creatinine</p><p>between days 2 and 5, with, respectively, 56.2 4 30.2</p><p>pmol/L and 49.3 -t 17.2 pmol/L. No nephrotoxicity</p><p>was observed in any of the patients.</p><p>DISCUSSION</p><p>The once-daily dosage regimen resulted in a higher</p><p>peak and a lower trough level. Of the patients 46%</p><p>and 14% had peaks of > 30 mg/L and > 40 mg/L,</p><p>respectively, and 100% had a trough < 2.5 mg/L on</p><p>day 2. No significant difference was noted between the</p><p>mean peak and trough amikacin serum concentrations</p><p>observed on days 2 and 5. There was no tendency for</p><p>amikacin accumulation during treatment. The mean</p><p>and individual peak amikacin levels in our study were</p><p>lower than those previously reported in adult patients</p><p>with severe infections [17,18] or in healthy young</p><p>Table 3</p><p>concentrations</p><p>Predictive performance of serum amikacin</p><p>MEd RMSEh</p><p>Trough (n = 35) -0.13 +1.70</p><p>Peak (n = 35) +1.37 +7.06</p><p>Peak + Trough (n = 70) +0.33 +5.10</p><p>(-0.88; +0.13)</p><p>(-0.99; +3.73)</p><p>(-2.02; +2.68)</p><p>"Mean prediction error (mg/L).</p><p>hRoot mean squared error (mg/L).</p><p>adult volunteers (23 to 31 years) [19] receiving a</p><p>similar dose of amikacin. These results could be</p><p>explained by a greater volume of distribution and a</p><p>more rapid total clearance in pediatric patients. These</p><p>results, however, are comparable with those observed</p><p>in critically ill patients over the age of 1 year (33.7 k</p><p>4.8 mg/L [ l l ] and in pediatric patients receiving</p><p>20 mg/kg who were suffering from severe Gram-</p><p>negative infections (36.5 4 9.1 mg/L [13]). However,</p><p>the once-daily dosage allows the maintenance of</p><p>higher aminoglycoside peak levels than conventional</p><p>regimens. Moore et al. [20] demonstrated in patients</p><p>with severe Gram-negative infections that a high peak</p><p>concentration relative to the MIC is a major</p><p>determinant of the clinical response to aminoglycoside</p><p>therapy. High peak levels are effective, because the</p><p>bactericidal activity of aminoglycosides is concentra-</p><p>tion dependent, but the ideal therapeutic peak has not</p><p>been defined. Beaucaire et al. [21] reported in</p><p>critically ill adults a significantly higher mortality rate</p><p>from infection when the first amikacin peak was below</p><p>40 mg/L. To achieve a peak value of 40 mg/L on the</p><p>first day of treatment, a loading dose is required,</p><p>especially in pediatric patients with large distribution</p><p>volume. This loading dose could correspond to 25%</p><p>of the daily dose [22]. Indeed, in neutropenic children</p><p>[12,23] and critically ill children [ l l ] , a dose of 20</p><p>mg/kg per day has been proposed.</p><p>We noted large interindividual variations in the</p><p>concentrations and pharmacokinetic parameters of</p><p>amikacin in pediatric patients. Therapeutic drug</p><p>monitoring early in treatment is thus necessary to</p><p>optimize dosage regimens. Predictive performance of</p><p>the Bayesian program can be enhanced when initial</p><p>population parameters reflect the patient population</p><p>being monitored. In clinical routine, monitoring of</p><p>aminoglycosides has been based on both the peak and</p><p>trough levels. The frequency of these measurements,</p><p>however, could be reduced to a single sampling.</p><p>Although trough concentrations are measured to avoid</p><p>aminoglycoside toxicity, it may be difficult to adjust</p><p>dosage on the basis of these concentrations, which are</p><p>currently below the limit of detection of the assay. In</p><p>neutropenic children undergoing bone marrow trans-</p><p>plantation receiving 20 mg/kg per day of amikacin,</p><p>serum concentrations declined rapidly and became</p><p>undetectable within 6 h [24]. Therefore, the serum</p><p>peak level seems the most appropriate sample for</p><p>monitoring. Sampling at other time intervals has been</p><p>proposed. Blaser et al. [25] reported a significant</p><p>correlation between nephrotoxicity and 8-h serum</p><p>netilmicin</p><p>concentrations. In comparison with serum</p><p>gentamicin concentrations 1 h and 8 h after the initial</p><p>administration, Bayesian analysis using the 4-h</p><p>190 Clinical Microbiology and Infection, Volume 2 Number 3 , December 1996</p><p>concentration was the least biased and the most precise</p><p>for predicting peak and trough concentrations [26].</p><p>However, these stuhes found no relationship between</p><p>the serum concentrations and therapeutic efficacy.</p><p>Our results regarding toxicity should be interpreted</p><p>cautiously. Nephrotoxicity was defined as a rise of</p><p>2 15% in serum creatinine, and no difference was noted</p><p>between days 2 and 5 . The higher trough concentra-</p><p>tions observed on day 5 (6.1 and 8.9 mg/L) were not</p><p>accompanied by an increase in serum creatinine, and</p><p>probably reflect wide intrapatient variability in</p><p>amikacin handling. The fiequency of nephro- and</p><p>ototoxicity seems to be lower in children than in adults</p><p>[24]. Other investigations to evaluate ototoxicity must</p><p>be performed.</p><p>In conclusion, once-daily dosage of amikacin (15</p><p>mg/kg per day), combined with another antimicrobial</p><p>agent, is well tolerated in pediatric patients. Serum</p><p>concentration monitoring early in treatment is essential</p><p>in children who show wide interpatient variability in</p><p>pharmacokinetic parameters. Moreover, as it seems that</p><p>the initial peak value is an important factor in clinical</p><p>outcome, a loading dose of 20 mg/kg per day is</p><p>recommended, in order to obtain satisfactory concen-</p><p>trations in most children. Drug monitoring will then</p><p>indicate whether or not dosage has to be reduced. This</p><p>approach provides security in achieving the best results</p><p>in children. Bayesian analysis is suitable for indi-</p><p>vidualization of amikacin dosage for pediatric patients.</p><p>Indeed, a single non-steady-state concentration is all</p><p>that is required to adjust dosage early in treatment,</p><p>preferably in the first 24 h.</p><p>Acknowledgments</p><p>This study was supported by the Bristol-Myers-Squibb</p><p>Company, Paris, France.</p><p>References</p><p>Maller R, Ahrne H, Eilard T, Eriksson I, Lausen I, the</p><p>Scandinavian amikacin once d d y study group. Efficacy and</p><p>safety of amikacin in systemic infections when given as a</p><p>single daily dose or in two divided doses. J Antimicrob</p><p>Chemother 1991; 27(suppl. C): 121-8.</p><p>Ter Braak EW, de Vries PJ, Bouter Kp, et al. Once-daily</p><p>dosing regimen for aminoglycoside plus R-lactam combina-</p><p>tion therapy of serious bacterial infections: comparative trial</p><p>with netilmicin plus ceftriaxone. Am J Med 1990; 89:</p><p>58-66.</p><p>Prins JM, Bdler HR, Kuijper EJ, Tange RA, Speelman l?</p><p>Once versus thrice d d y gentamicin in patients with serious</p><p>infections. Lancet 1993; 341: 335-9.</p><p>Siege1 JD, McCracken GH, Thomas ML, Threkeld N.</p><p>Pharmacokinetic properties of netilmicin in newborn</p><p>infants. Antimicrob Agents Chemother 1979; 15: 246-53.</p><p>5. Schevuk Y, Taylor D. Aminoglycosides, volume of distribu-</p><p>tion in pematrics patients. Ann Pharmacother 1990; 24:</p><p>273-6.</p><p>6. Zaske DE, Cipolle RJ, Rotschafer JC, Kohls PR, Strate RG.</p><p>Individualizing amikacin regimens: accurate method to</p><p>achieve therapeutic concentrations. Therapeutic Drug</p><p>Monitoring 1991; 13: 502-6.</p><p>7. Carlsted BC, Uaamnuichi M, Day FU3, Bowman L, Brater</p><p>DC. Ammoglycoside dosing in pediatric patients. Ther</p><p>Drug Monit 1989; 11: 38-43.</p><p>8. 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C): 113-20.</p><p>25. Blaser J, Konig C, Simmen HP, Thurnheer U. Monitoring</p><p>serum concentrations for once-daily netilmicin dosing</p><p>regimens. J Antimicrob Chemother 1994; 33: 341-8.</p><p>26. Chrystyn H. Validation of the use of Bayesian analysis in the</p><p>optimization ofgentamicin therapy &om the commencement</p><p>of dosing. Drug Intell Clin Pharmacol 1988; 22: 49-53.</p><p>Pharmacokinetics of once-daily arnikacin in pediatric patients</p><p>MATERIALS AND METHODS</p><p>Patient selection</p><p>Drug administration and dosage</p><p>Evaluation of nephrotoxicity</p><p>Bayesian forecasting of dosage</p><p>Predictive analysis</p><p>RESULTS</p><p>DISCUSSION</p><p>Acknowledgments</p><p>References</p>