[in Japanese]

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[in Japanese]

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Twenty-one children, from 41 hours to 12 years of age, were given amikacin (AMK) for suspected bacterial infections. In the 41 hours old newborn infant, the half-life of AMK was 6.9 hours. As infants' ages increase, half-lives of AMK became shorter. The trend toward a shorter half-life in an older child was the most marked during neonatal period. At an age of 7 days, the half-life was shorter than 3 hours. In infants exceeding 6 months of age, ages did not make differences in the length of half-lives.
The apparent volume of distribution in newborn was, as average, 350.6 ml/kg body weight.The average for children 5 years and older was smaller, 280.7 ml/kg.
The peak level-dose ratio was 2.8 (μg·ml^-1·mg^-1·kg) in newborns. There was a tendency that this ratio increased with age. The average ratio for children over 5 years was 4.5 (μg·ml^-1·mg^-1·kg).
In summary, the 2 remarkable observations obtained from the present study were; 1) The trend that the half-life of AMK shortens as the child grows older was clearest in neonatal period. 2) Peak serum level produced by the same dose per kilogram body weight had a tendency to increase with ages of children.

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Amikacin (AMK) is one of the aminoglycoside antibiotics, derived from kanamycin A. It has a broad spectrum against Gram-negative rods but its usefulness is mainly in the efficacy against Gram-negative rods which do not respond to commonly used kanamycin and gentamicin.
The efficacy and the safety of AMK have been confirmed in children and mature babies.
In the trial reported here, we evaluated AMK in newborn.
1. AMK was administered to 13 mature and 8 premature babies via intramuscular injection or intravenous drip infusion for 30 minutes or 1 hour and its blood concentrations were determined.
These administrations resulted in blood concentrations 4.47-9.67 mcg/ml with dosage levels 2-3 mg/kg (mean 6.92±1.66 mcg/ml), 5.86-26.1 mcg/ml with 5-6 mg/kg (mean 15.4±4.63 mcg/ml) and 27.5-37.7 mcg/ml with 7.5 mg/kg (mean 31.0±4.76 mcg/ml). Blood half-lives were 1.88 to 9.66 hours, showing longer half-lives in younger subjects.
2. Exchange transfusion (150-180 ml/kg) was performed in 5 mature babies and the variation of blood concentrations of AMK was studied. The study showed that blood concentrations of AMK after the exchange transfusion were 25.6-41.5% (mean 32.3±5.4%) of the levels detected before the transfusion.

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A pharmacokinetic study was conducted in neonates (mature, premature) to which amikacin (AMK) was administered through intravenous drip infusion. The results of the study are summarized below.
1. Changes in blood concentrations of AMK obtained after intravenous drip infusion over a period of 30 or 60 minutes were comparable to those after intramuscular injection.
2. When AMK was administered to neonates (mature, premature) at a single intravenous (30 or 60 minutes) dose of 6 mg/kg, peak levels of 15.5 to 26.3 μg/ml were attained. These values were within the range of 15 to 30 μg/ml which are considered to be safe and effective peak levels.
3. In 0 day-neonates, half-lives of blood AMK levels rather long and widely varied (3 to 8 hours) but, in about 7 day-neonates, half-lives were 3 to 4 hours.
4. It is considered from the above results that the safe and effective blood concentrations of AMK in 0 to 7 day-old neonates can be obtained from intravenous administrations at each dose of 6 mg/kg repeated with intervals of 12 or 24 hours and, in 8 days or older neonates, from intravenous drip infusions over 30 or 60 minutes at each dose of 6 mg/kg repeated with intervals of 12 hours.
5. For neonates with very low birth weights, individual doses and intervals should be separately investigated.

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Amikacin (AMK) was administered mainly to neonates by either intravenous drip infusion or intramuscular injection and its pharmacokinetic changes were investigated. The results obtained are summarized as follows.
1. Serum half-lives of AMK in neonates at ages 0 to 3 days were longer than those at ages 4 to 10 days. Serum half-lives were prolonged particularly in neonates at an age 0 day. Neonates at ages 11 to 15 days, also showed longer half-lives in comparison to infants. Similar peak serum levels were observed in al. the neonates with ages 0-15 days.
2. Similar serum AMK levels were obtained in neonates through intravenous drip infusion and through intramuscular injection at a same dose level.
3. When the drug was administered to neonates at 3.0 to 6.0 mg/kg by intravenous drip infusion, peak serum levels did not reach 30 μg/ml which is considered to be the critical level for AMK to be toxic.
4. Urinary excretion rates in neonates 11 day or older were almost the same levels as in infants.
5. AMK, when administered through intravenous drip infusion, was observed to have a higher migration rate to saliva when compared with kanamycin administered through intramuscular injection.
6. Based on the results obtained from the present study, the following doses seem to be optimal for neonates, but further studies are required to be conclusive.
For neonates: 2.0 to 5.0 mg/kg daily in 1 to 2 divided doses.(For those at ages of 0 to 3 days: 2.0 to 3.0 mg/kg)
For infants: 3.0 to 8.0 mg/kg daily in 1 to 2 divided doses through intravenous drip infusion over a period of 30 minuws to 1 hour.

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Sixteen neonates (at ages of 8 to 28 days) and 8 infants (at ages of 35 days to 1 year), who were in need of treatment with amikacin sulfate, were subjected to the present study.The drug was administered by intramuscular route (1.39 to 3.13 mg/kg) or by intravenous drip infusion over a 30 to 60 minutes period (2.94 to 6.00 mg/kg). Blood levels and urinary excretion of the drugwere investigated with these subjects. The blood levels were also analyzed according to pharmacokinetic models.
1. When the drug was administered intramuscularly to neonates at average doses of 1.49 and 2.96 mg/kg and to infants at average doses of 2.97 mg/kg peak levels of 2.74, 6.53 and 8.55 μg/ml, respectively, were attained at 30 minutes after dosing.
2. When the drug was administered to neonates at average doses of 3.01 and 5.89 mg/kg byintravenous drip infusion over a 30 to 60 minutes period and to infants at average doses of 2.97 and 6.00 mg/kg in the same manner, peak levels of 7.70, 20.9, 9.40 and 23.0μg/ml, respectively, were attained at the end of the intravenous drip infusion.
3. Urinary levels and recovery rates tended to increase with ages of these subjects. Urinary recovery rates for the neonates and the infants were 41.0 and 58.9%, respectively, on the average.
4. From a pharmacokinetic analysis of blood levels of the drug, it was concluded that, in any of the subjects who received the drug intramuscularly or by intravenous drip infusion, it would be possible to use the one-compartment open model. In the subjects who received the drug by intravenous drip infusion, however, it was determined the two-compartment open model would be the choice.
5. In the neonates and the infants, whose blood levels were analyzed according to the one-compartment open model, Ka values averaged 7.51 and 6.62 hr^-1, respectively, with respective average Kel values of 0.32 and 0.66 hr^-1. Average Vd values obtained were 0.36 and 0.26 L/kg, respectively. There was a negative correlation between the Vd values and the ages of the subjects, while there was a positive correlation between the Kel values and the ages.
6. Appropriate conditions for administering the drug by intravenous drip infusion to neonates and infants at ages of more than 1 week were investigated taking observed blood levels and achieved peak levels and trough levels calculated using the one-compartment open model into account. It was concluded that intravenous drip infusion over a 30 to 60 minutes period would be the choice and the use of the drug should be within a limit of 3 times daily at a single dose not exceeding 6 mg/kg.

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Amikacin (AMK) was intravenously administered to pediatric surgical patients, and its pharmacokinetics was studied. The results obtained are summarized as follow:
1. The serum levels following administration were similar to those which had been reported by others. Urinary excretion was excellent.
2. The concentration of AMK in pleural effusion of a postoperative premature baby was an effective level higher than MIC's to target organisms.
3. Bile levels of AMK were the highest soon after surgery on patients with biliary atresia, these declined as time passed. The high levels obtained were in the effective range where the levels were higher than MIC's against organisms isolated from bile of patients with biliary tract infections. Biliary excretions were good in cases with good hepato-enteric circulation.
4. Biliary and urinary excretion rates were well correlated.

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Pharmacokinetic and clinical studies on amikacin (AMK) were performed in neonates and the results obtained are summarized as follows.
1. After intramuscular injection of single doses of AMK at 3 mg/kg, peak serum levels were 6.8 μg/ml in a 2-day-old neonate and 7.0 μg/ml in a 20-day-old neonate. Serum levels of AMK in the above 2 neonates at 8 hours after injection were 1.5 μg/ml and 1.4 μg/ml, respectively, and the half-life of AMK was 3.3 hours. After intramuscular injection of single doses of 4 mg/kg of AMK, the mean peak serum level was 8.1±1.1 μg/ml, and half-lives of AMK were 6.1 hours in a 1-day-old neonate and 4.0 hours in a 3-day-old neonate. The mean peak serum level of AMK reached at 1 hour after intramuscular administrations at single dose of 6 mg/kg was 10.5±0.5 μg/ml in a 3-day and a 4-day-old neonates. Serum levels at 8 hours after administrations were 3.1 μg/ml and 2.8 μg/ml, in the 3-day and the 4-day-old neonates, respectively. Half-lives of AMK in sera were 3.9 hours in the 3-day-old neonate and 3.5 hours in the 4-dayold neonate.
2. In three 2-day-old neonates, the mean peak serum level of AMK after an intravenous drip infusion for 30 minutes at single dose of 3 mg/kg was 10.0±1.1 μg/ml at the end of infusion and serum levels decreased to 2.3+0.6 μg/ml at 6.5 hours after infusion. The mean serum half-life of AMK was 3.1 hours. In an 8-day-old neonate, the peak serum level was 6.2 μg/ml at the end of infusion, andl serum levels at 1.5 hours and 6.5 hours were 4.2 μg/ml and 1.4 μg/ml, respectively. The half-life was 3.1 hours. In 2 neonates, 1-day-old and 3-day-old, the mean peak serum level of AMK after intravenous drip infusion for 30 minutes at single doses of 6 mg/kg was 16.4±3.9 μg/ml at the completion of an infusion, and serum levels decreased to 3.5±0.8 μg/ml at 6 hours after the end of infusion. The mean half-life of AMK was 2.9 hours. In a 5-day-old neonate, serum levels were 13.5 μg/ml at the completion of infusion and 2.6 μg/ml at 6 hours; the half-life was 2.4 hours.
3. Urinary excretion rates were 35.4%, 56.7%, 18.4% in 8 hours after intramuscularinjection of 3 mg/kg, 4 mg/kg, 6 mg/kg of AMK, respectively. Mean urinary excretion rates of AMK were 40.8% and 13.1% in 6 hours after intravenous drip infusion for 30 minutes of 3 mg/kg and 6 mg/kg of AMK, respectively.
4. AMK was given to 1 case with genital abscess. Daily dose of AMK was 9 mg/kg. Good responses were obtained clinically and bacteriologically.

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The use of amikacin (AMK) in newborns was investigated and the results obtained are summarized as follows.
1. AMK was administered to 3 rabbits at an intramuscular dose of 6 mg/kg. Mean blood levels determined according to methods of bipassay (BIO) and fluorescent immunoassay (FIA) were 28.6 and 22.2 μg/ml, respectively, at 30 minutes after dosing. Then, the blood levels declined rapidly. Mean T 1/2 values obtained with the above 2 assay methods were 0.76 and 0.63 hours, respectively.
2. When AMK was administered at a dose of 5.7 mg/kg to a 64 day-old newborn by drip intravenous infusion for 30 minutes, a peak blood level was attained at the end of drip intravenous infusion, which was 20.0 μg/ml according to BIO and was 15.5 μg/ml according to FIA. The blood levels declined gradually thereafter with a T 1/2 value of 2.33 hours (BIO) or 2.03 hours (FIA). When the drug was administered at 5.3 mg/kg to a 26 day-old newborn using the same infusion method, the peak blood level obtained at the end of drip intravenous infusion was 18.0 μg/ml according to BIO and was 14.8 μg/ml according to FIA, and T 1/2 values were 4.76 and 3.68 hours, respectively.
3. As there was a close correlation between the values obtained with BIO and with FIA in both rabbits and clinical cases, with a coefficient of 0.990, and also the BIO values could be estimated using a formula of FIA value × 1.2+2.2, it would be possible to monitor AMK levels in the blood of patients at bedside using the FIA.
4. To 2 newborn patients at 61 and 23 days of age with urinary tract infections due to AMKsensitive E. coli, AMK was administered at a daily dosage of 18.3 and 17.1 mg/kg, respectively, in 3 divided doses by drip intravenous infusion for 30 minutes over a 6-day period. Excellent responses were obtained in both cases. Neither adverse clinical symptoms nor abnormal audiometrical findings were observed in either of the 2. As abnormal laboratory findings, an elevation in GOT and GPT levels was found in 1 but was only transient and was only slight.

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To evaluate pharmacokinetics of amikacin (AMK), one of the aminoglycoside antibiotics, children with ages from 2 days to 11 years were treated with various doses by various administration routes, and both plasma and urinary levels of AMK were determined. The following is a summary of the results obtained:
1. Of 6 children, three were treated with 2.0 mg/kg of AMK by a 30-minute intravenous drip infusion, and the other 3 with 4.0 mg/kg by a 60-minute.
Peaks of average plasma levels were observed at the ends of the infusions in both cases, and their levels were 9.23 and 13.67μg/ml, respectively, showing a dose-dependency.
Both half-lives and areas under plasma concentration-time curves (AUCs) were similar to those of adults. However, the volume of distribution (Vd) showed a lower value than that of adults. Peaks of average urine levels were 149.3μg/ml with 2.0 mg/kg in 0-2 hours after the start of the infusion and 223.3μg/ml with 4.0 mg/kg in 2-4 hours. Average urinary recovery rates within 6 hours after the start of the infusion were 95.4% with 2.0 mg/kg and 85.7% with 4.0 mg/kg.
These recoveries were equal to or higher than that of adults.
2. When 3.0, 4.0 and 6.0 mg/kg of AMK were administered to 3 groups of mature or premature babies by intramuscular injection, average peak levels of AMK in plasma were 6.26, 8.61 and 12.60μg/ml, respectively, at 30 minutes after the injection, showing dose-dependency. In these groups, the younger the day age after birth was, the longer the half-life became. The AUCs were larger as the half-life became longer. The Vd was larger than that in the intravenous drip infusion group, but, any particular was not observed. Average peak levels of AMK in urine were 78.83μg/ml at 4-6 hours with a dose level of 3.0 mg/kg, 99.17μg/ml at 2-4 hours with 4.0 mg/kg and 139.20μg/ml at 0-2 hours with 6.0 mg/kg. Average urinary recovery rates within 6 hours were 36.57% with 3.0 mg/kg, 34.67% with 4.0 mg/kg and 43.77% with 6.0 mg/kg. These recovery rates were markedly lower than those observed in adults and children. One of the causes of this low recovery is that mature and premature babies have immature renal functions.
3. When 3.0 mg/kg of AMK was administered to three premature babies by a 30-m inute intravenous drip infusion, the average peak plasma levels was 7.61μg/ml at the end of the drip infusion. This level was similar to that after an intramuscular injection of the same dose level in mature and premature babies. The longer half-life was observed in those babies with younger day-age or with smaller body weight. AUCs became larger as half-lives were longer. The Vd was larger than that in children treated by intravenous drip infusion. Statistical significance was not observed, however.
When 6.0 mg/kg of AMK was administered to a mature baby by a 30-minute intravenous drip infusion, the peak plasma level was 14.1μg/ml at the end of the drip infusion. It was slightly higher than the average peak plasma level in premature babies treated with 6.0 mg/kg by an intramuscular injection. A dose-dependency was observed in 3.0 and 6.0 mg/kg dose groups with 30-minute intravenous drip infusion. The half-life was 1.84 hours, which was al ittle longer than that of children treated with intravenous drip infusion.
The Vd in the premature babies was larger than that in children studied. When 6.0 mg/kg of AMK was administered to 2 premature babies by a 60-minute intravenous drip infusion, the average peak levels of plasma concentration was 17.6μg/ml reached at the end of the infusion. This level was higher than that of premature babies treated with the same dose by an intramuscular injection or that of premature babies treated by a 30-minute intravenous drip infusion. The half-life was slightly longer, and as the half-life became longer, AUC and Vd became larger than those in children administered with AMK by intravenous drip infusion.

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