Pharmacokinetics and pharmacodynamics of intravenous meperidine in neonates and infants.

The pharmacokinetics of meperidine (pethidine) was studied in 21 infants who received a single intravenous dose of 1 mg/kg after surgery (n = 18) or during mechanical ventilation because of respiratory distress (n = 3). Eleven patients were younger than 1 week old, 10 patients were aged from 3 weeks to 5 months, and five of the patients were premature. The pharmacokinetics of meperidine varied greatly between the subjects, with a median elimination half-life of 10.7 hours (range, 3.3 to 59.4 hours), median clearance of 8.0 ml/kg/min (range, 1.8 to 34.9 ml/kg/min), median volume of the central compartment of 2.4 L/kg (range, 0.5 to 4.8 L/kg), and median steady-state volume of distribution 7.2 L/kg (range, 3.3 to 11.0). The great interindividual variability in meperidine pharmacokinetics should be taken into consideration when meperidine is administered to neonates. Although no life-threatening or serious side effects were observed in this study, appropriate care should be exercised when prescribing meperidine for this age group.     

Pharmacokinetics and renal tolerance of aztreonam in premature infants.

Aztreonam (30 mg/kg of body weight) was administered intravenously over 3 min every 12 h to 30 preterm neonates divided into two groups according to gestational age (mean age for group A was less than 30 weeks and mean age for group B was greater than 30 weeks) and birth weight (mean weight for group A was less than 1,500 g and mean weight for group B was greater than 1,500 g). Blood and urine samples were analyzed by microbiological assay. The pharmacokinetics were described by one-compartment and noncompartment models. The mean half-life and clearance for premature infants weighing less than 1,500 g were 5.33 +/- 3.61 h and 1.52 +/- 1.33 ml/min/kg, respectively; for those weighing more than 1,500 g, the values were 4.08 +/- 2.28 h and 2.41 +/- 2.10 ml/min/kg, respectively. The mean urinary concentration of aztreonam in 15 premature infants during the first 6 h of therapy was 242.72 +/- 188.19 micrograms/ml, with a mean percentage of elimination of 13.29%. Urinary excretion of N-acetyl-beta-D-glucosaminidase (a specific and sensitive test for the detection of drug-induced renal tubule damage) did not show significant differences in our group of premature infants compared with that in a control group. The dose of 30 mg/kg and a dosage interval of 8 to 12 h could be recommended for the treatment of suitable bacterial infections in all premature infants.     

Pharmacokinetics of imipenem-cilastatin in neonates.

Imipenem and its renal dehydropeptidase I inhibitor, cilastatin, were coadministered intravenously in a 1:1 ratio to 30 newborns. Five infants each received single doses of 10, 15, or 20 mg/kg of both drugs. Concentrations in plasma were proportional to the administered dose, and cilastatin achieved consistently higher concentrations than did equivalent doses of imipenem because of its smaller volume of distribution. The pharmacokinetics of both drugs were best described by a one-compartment model. The plasma half-lives of imipenem were 1.7 to 2.4 h, whereas those of cilastatin were 3.9 to 6.3 h. The plasma clearance of cilastatin was approximately one-quarter of that of imipenem in the dose range tested. The urinary concentrations of imipenem were 50% of those of cilastatin despite its higher clearance from plasma. Fifteen additional newborns received five to eight doses of imipenem-cilastatin at 20 mg/kg per dose every 12 h. There was no accumulation of either drug in plasma after repeated administrations, and the mean concentrations in plasma were similar when measured on the first and last days of the multiple-dose study. There was marked intersubject variability, more so for cilastatin. The pharmacokinetics of both drugs in neonates resembled those observed in adults with moderate to severe renal insufficiency. Because the effects of enzyme inhibition on neonates are unknown, additional studies with imipenem-cilastatin (primaxin) are recommended.     

Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis

Acyclovir is approved for the treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections in children by the intravenous and oral routes. However, its use by the oral route in children younger than 2 years of age is limited due to a lack of pharmacokinetic data. The objectives of the present study were to determine the typical pharmacokinetics of an oral suspension of acyclovir given to children younger than 2 years of age and the interindividual variabilities in the values of the pharmacokinetic parameters in order to support the proposed dosing regimen (24 mg/kg of body weight three times a day for patients younger than 1 month of age or four times a day otherwise). Children younger than age 2 years with HSV or VZV infections were enrolled in a multicenter study. Children were treated for at least 5 days with an acyclovir oral suspension. Plasma samples were obtained at steady state, before acyclovir administration, and at 2, 3, 5, and 8 h after acyclovir administration. Acyclovir concentrations were measured by radioimmunoassay. The data were analyzed by a population approach. Data for 79 children were considered in the pharmacokinetic study (212 samples, 1 to 5 samples per patient). Acyclovir clearance was related to the estimated glomerular filtration rate, body surface area, and serum creatinine level. The volume of distribution was related to body weight. The elimination half-life decreased sharply during the first month after birth, from 10 to 15 h to 2.5 h. Bioavailability was 0.12. The interindividual variability was less pronounced when the parameters were normalized with respect to body weight. Hence, dosage adjustment by body weight is recommended for this population. Simulations showed that the length of time that acyclovir remains above the 50% inhibitory concentration during a 24-h period was more than 12 h for HSV but not for VZV. The proposed dosing regimen seems adequate for the treatment of HSV infections, while for the treatment of VZV infections, a twofold increase in the dose seems necessary for children older than age 3 months.     

Pharmacokinetics of cefoperazone in full-term and premature neonates.

The pharmacokinetics of cefoperazone were evaluated in 28 newborn infants who were being treated for sepsis. A dose of 50 mg/kg was administered intravenously on days 0 to 2 in all, with a second dose administered on days 5 to 7 in 14 infants. Cerebrospinal fluid penetration was also studied in seven neonates. The mean peak concentration of cefoperazone in the serum of premature infants less than 33 weeks of gestational age, 159 (standard deviation, +/- 22) micrograms/ml, was higher than concentrations in premature infants 33 to 36 weeks of age and full-term infants (110 +/- 41 and 109 +/- 29 micrograms/ml, respectively). The mean concentrations 24 h after dosage were similar in all three groups, 13 to 17 micrograms/ml. The mean serum half-lives were similar in the three subgroups and ranged from 7 to 9 h. After the dose at 5 to 7 days, mean blood levels in the subgroups at 0.5 h were 149, 112, and 112 micrograms/ml; 24-h levels ranged from 9 to 12 micrograms/ml. The mean serum half-lives ranged from 5 to 7 h. Cerebrospinal fluid levels in patients with meningitis ranged from 2.8 to 9.5 micrograms/ml and in patients without meningitis from 1 to 7 micrograms/ml. Peak blood levels were 15 to 1,000 times higher than the 90% minimal inhibitory concentration of common pathogens found in newborns. These observations support the potential efficacy of cefoperazone in treatment of infections, including meningitis, in newborn infants.     

卡泊芬净在新生儿及不足3月龄婴儿中的药动学和安全性研究

念珠菌感染在新生儿监护室,特别是对于极低体重（〈1500g）新生儿是一个主要威胁。迟发性脓毒血症在重症患儿及低体重新生儿的患病率约为20％,其中至少10％的感染由念珠菌引起。     

Pharmacokinetics of cefotaxime in neonates

The effects of gestational age on the pharmacokinetics of cefotaxime and its desacetyl metabolite during the first days of life was investigated in a group of four full-term infants and 12 preterm infants of less than 35 weeks gestation. Half of the preterm infants had received betamethasone, a drug known to facilitate hepatic microsomal drug metabolism, whilst the others had not. No significant differences in the pharmacokinetics of cefotaxime were observed between the various groups, with elimination half-life (T 1/2 beta) of cefotaxime ranging from 4.04 +/- 1.52 to 4.56 +/- 1.31 h. The desacetyl metabolite of cefotaxime was present in all post-dose serum samples, irrespective of the gestational age of the baby. Its formation was apparently unaffected by prior exposure to betamethasone. The elimination half-life of cefotaxime is significantly longer in newborn infants than in older children or adults, this increase probably results from decreased renal excretion of the drug, rather than from immaturity in its metabolism. A dose of 50 mg/kg of cefotaxime given every 12 h is appropriate for infants of less than seven days old.     

Pharmacokinetics of cefprozil in infants and children.

Twenty pediatric patients (ages, between 8 months and 8 years) received a single oral dose of cefprozil at levels of 15 and 30 mg/kg of body weight. Cefprozil consists of cis (BMY-28100) and trans (BMY-28167) isomers in an approximately 90:10 ratio. Six plasma samples were collected from each pediatric patient and assayed for drug concentrations. As measured by a microbiological assay, peak concentrations of 11.16 and 15.93 micrograms of cefprozil per ml occurred at 1 h for patients who received the 15- and 30-mg/kg doses, respectively. The respective mean half-lives of cefprozil were 1.77 and 2.14 h, and the respective mean areas under the curve were 28.05 and 45.28 micrograms.h/ml for patients who received the 15- and 30-mg/kg doses. When measured by a high-pressure liquid chromatography method, peak concentrations of 12.09 and 18.04 micrograms of the cis isomer per ml were obtained at 1 h, with mean half-lives of 1.63 and 2.06 h and mean areas under the curve of 30.48 and 49.34 micrograms.h/ml in patients who received the 15- and 30-mg/kg doses, respectively. For the trans isomer, peak concentrations of 1.16 and 1.63 micrograms/ml occurred at 1 h, respectively, with mean half-lives of 1.61 and 1.65 h and mean areas under the curve of 2.89 and 4.34 micrograms.h/ml in patients who received the 15- and 30-mg/kg doses, respectively.     

Pharmacokinetics of cefotaxime in newborn infants.

The pharmacokinetics of cefotaxime were determined in newborn infants who were 1 to 7 days of age. Mean peak serum concentrations of 116 and 132 micrograms/ml were observed at completion of a 10-min intravenous infusion of 50 mg of cefotaxime per kg in low and average birth weight infants, respectively. The mean elimination half-lives were 4.6 and 3.4 h and rates of clearance from serum were 23 and 44 ml/min per 1.73 m2, respectively. A dosage schedule for cefotaxime in newborn infants is presented.     

Pharmacokinetics of ceftazidime in newborn infants.

Doses of 50 mg of ceftazidime per kg were administered intravenously to 29 newborn infants every 8 or 12 h for 3 to 5 days. Mean peak concentrations in plasma ranged from 102 to 124 micrograms/ml. Mean elimination half-life values ranged from 2.9 to 6.7 h and varied inversely with gestational age and plasma clearances. Peak and trough plasma bactericidal titers against an Escherichia coli and a group B streptococcus strain were at least 1:16 and 1:32, respectively.     

Pharmacokinetics and absolute bioavailability of phenobarbital in neonates and young infants,a population pharmacokinetic modelling approach

Phenobarbital is widely used for treatment of neonatal seizures. Its optimal use in neonates and young infants requires information regarding pharmacokinetics. The objective of this study is to characterize the absolute bioavailability of phenobarbital in neonates and young infants, a pharmacokinetic parameter which has not yet been investigated. Routine clinical pharmacokinetic data were retrospectively collected from 48 neonates and infants (weight: 0.7–10 kg; patient's postnatal age: 0–206 days; GA: 27–42 weeks) treated with phenobarbital, who were administered as intravenous or suspension by oral routes and hospitalized in a paediatric intensive care unit. Total mean dose of 4.6 mg/kg (3.1–10.6 mg/kg) per day was administered by 30‐min infusion or by oral route. Pharmacokinetic analysis was performed using a nonlinear mixed‐effect population model software). Data were modelled with an allometric pharmacokinetic model, using three‐fourths scaling exponent for clearance (CL). The population typical mean [per cent relative standard error (%RSE)] values for CL, apparent volume of distribution (V_d) and bioavailability (F) were 0.0054 L/H/kg (7%), 0.64 L/kg (15%) and 48.9% (22%), respectively. The interindividual variability of CL, V_d, F (%RSE) and residual variability (%RSE) was 17% (31%), 50% (27%), 39% (27%) and 7.2 mg/L (29%), respectively. The absolute bioavailability of phenobarbital in neonates and infants was estimated. The dose should be increased when switching from intravenous to oral administration.     

Pharmacokinetics of LY163892 in infants and children.

Two dosages (7.5 and 15 mg/kg of body weight) of LY163892 were given to infants and children, and five plasma specimens were collected for antibiotic assay during the ensuing 4 h. Peak concentrations of 12.6 and 18.7 micrograms/ml occurred at 45 min. The mean half-lives were 0.85 and 0.78 h, and the mean areas under the curve were 24.4 and 38.0 micrograms.h/ml.     

Pharmacokinetics of acyclovir suspension in infants and children.

Eighteen children from 3 weeks to 6.9 years of age were given an oral acyclovir suspension for herpes simplex or varicella-zoster virus infections. Thirteen patients who were 6 months to 6.9 years old received 600 mg/m2 per dose, and three infants and two children less than 2 years old were given 300 mg/m2 per dose. The drug was given four times a day, except to one infant who was treated with three doses a day. Among the 13 children who received the 600-mg/m2 dose, the maximum concentration in plasma (Cmax) was 0.99 +/- 0.38 microgram/ml (mean +/- standard deviation), the time to maximum concentration (Tmax) was 3.0 +/- 0.86 h, the area under the curve (AUC) was 5.56 +/- 2.17 micrograms.h/ml, and the elimination half-life (t1/2) was 2.59 +/- 0.78 h. The three infants less than 2 months of age who received the 300-mg/m2 dose had a Cmax of 1.88 +/- 1.11 micrograms/ml, a Tmax of 4.10 +/- 0.48 h, an AUC of 6.54 +/- 4.32 micrograms.h/ml, and a t1/2 of 3.26 +/- 0.33 h. The acyclovir suspension was well tolerated by young children. No adverse effects requiring discontinuation of the drug occurred.     

Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation.

Extracorporeal membrane oxygenation (ECMO) has been used in more than 1,000 infants in 50 centers in the United States. The extracorporeal circuit contains approximately 400 ml of blood, an amount exceeding the blood volume of most full-term neonates. The effect of this additional blood volume on drug disposition is unknown. In this study, we determined the pharmacokinetic parameters of gentamicin in 10 infants on ECMO. Gentamicin concentrations were determined by a fluorescence polarization immunoassay. Pharmacokinetic parameters were determined from these concentrations by using a two-compartment model. Our study demonstrated a mean steady-state volume of distribution of 0.51 +/- 0.11 liters/kg, a figure similar to that in previous studies of full-term infants. The elimination half-life was found to be prolonged (mean, 573 +/- 263 min). The creatinine level in the plasma of the infants was found to be a statistically significant predictor of elimination half-life. Recommendations regarding initial dosing levels of gentamicin in infants on ECMO are made.     

Pharmacokinetics and metabolism of intravenous midazolam in preterm infants.

BACKGROUND: Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants. METHODS: The pharmacokinetics of midazolam and its hydroxylated metabolite (1-OH-midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1-OH-midazolam concentrations were determined by use of gas chromatography-mass spectrometry. RESULTS: Total body clearance, apparent volume of distribution, and plasma half-life of midazolam were (median [range]): 1.8 (0.7-6.7) ml/kg per min, 1.1 (0.4-4.2) L/kg, and 6.3 (2.6-17.7) h, respectively. In 19 of 24 preterm infants, 1-OH-midazolam concentrations could be detected: 1-OH-midazolam (1-OH-M) maximal concentration of drug in plasma (C(max)), time to reach C(max) (T(max)), and 1-OH-M/M area under the concentration-time curve from time zero to the last sampling time point (AUC(0-t)) ratio were [median (range)]: 8.2 (<0.5-68.2) ng/ml, 6 (1-12) h, and 0.09 (<0.001-1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure. DISCUSSION: Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1-OH-midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.     

Pharmacokinetics of a clarithromycin suspension in infants and children.

The single- and multiple-dose pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite in infants and children were studied after oral administration under fasting and nonfasting conditions. Drug absorption appeared to be rapid following a brief delay in its onset; the mean peak concentrations in plasma (Cmax) for clarithromycin were reached within about 3 h under both conditions. The mean Cmax for the parent drug were 3.59 and 4.58 micrograms/ml in single-dose fasting and nonfasting patients, and the respective Cmax for the metabolite were 1.19 and 1.26 micrograms/ml. Data indicate good absorption and no significant effects by food. There was no unusual accumulation in the area under the concentration-time curve and Cmax in the multiple-dose group.     

Pharmacokinetics of cefuroxime axetil suspension in infants and children.

The pharmacokinetics of cefuroxime axetil suspension in 28 infants and children, ranging in age from 3 months to 12 years (mean, 23 months), were studied. Mean maximum serum cefuroxime concentrations of 3.3, 5.1, and 7.0 micrograms/ml were achieved 3.6, 2.7, and 3.1 h after the administration of doses of 10, 15, and 20 mg, respectively, of cefuroxime axetil suspension per kg of body weight together with milk or milk formula. These concentrations exceed the MICs for common respiratory tract pathogens, including beta-lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis. Following a 10- or 15-mg/kg dose, serum cefuroxime concentrations are similar to those achieved in adults following the administration of a 250-mg cefuroxime axetil tablet. There were linear relationships between dose and both maximum serum cefuroxime concentration and area under the serum drug concentration-verus-time curve. The mean half-life of cefuroxime in serum was independent of dose and ranged from 1.4 to 1.9 h. No cefuroxime axetil (intact ester) was detected in the blood. The intact ester in the urine of four children was measured; however, the amount recovered represented less than 0.1% of the administered dose.     

Pharmacokinetics of penicillin g in very-low-birth-weight neonates

Data on the pharmacokinetics (PKs) of penicillin G (PEN) in neonates date back to the 1970s and do not include data for very-low-birth-weight (VLBW) neonates. The aim of this study was to describe the steady-state PKs and to establish an optimal regimen for the dosing of PEN in neonates with gestational ages of less than 28 weeks and birth weights of less than 1,200 g. Two PEN dosing regimens were studied: 50,000 IU (30 mg)/kg of body weight every 12 h (q12h) (group 1; n = 9) and 25,000 IU (15 mg)/kg q12h (group 2; n = 9). Samples for PK analysis were drawn before the injection of PEN and at 2 and 30 min and 1.5, 4, 8, and 12 h after intravenous injection of the third to eighth PEN doses. The PEN concentration was measured by a high-performance liquid chromatography with UV detection technique. The median peak and trough concentrations of PEN were 147 mug/ml (lower and upper quartiles, 109 and 157 mug/ml, respectively) and 7 mug/ml (lower and upper quartiles, 5 and 13 mug/ml, respectively) after administration of the dose of 50,000 IU and 59 mug/ml (lower and upper quartiles, 53 and 78 mug/ml, respectively) and 3 mug/ml (lower and upper quartiles, 3 and 4 mug/ml, respectively) after administration of the dose of 25,000 IU. The PEN half-life (median and lower and upper quartiles for group 1, 3.9 h and 3.3 and 7.0 h, respectively; median and lower and upper quartiles for group 2, 4.6 h and 3.8 and 5.6 h, respectively) was longer in VLBW neonates than in adults and term infants. PEN renal clearance correlated with creatinine clearance (R(2) = 0.309596; P = 0.038). Only a median of 34% (lower and upper quartiles, 28 and 37%, respectively) of the administered dose was excreted in urine within the following 12 h. We conclude that in VLBW infants a PEN dose of 25,000 IU (15 mg)/kg q12h is safe and sufficient to achieve serum concentrations above the MIC(90) for group B streptococci for the entire dosing interval.