Pediatric Infectious Disease Journal:
Linezolid pharmacokinetics in pediatric patients: an overview
JUNGBLUTH, GAIL L. PhD; WELSHMAN, IAN R. MS; HOPKINS, NANCY K. BS
From the Clinical Pharmacology Unit, Pharmacia Corp., Kalamazoo, MI.
Reprints not available.
Background. There are a number of physiologic and developmental differences between children and adults that can influence the absorption, distribution, metabolism and elimination of a drug. Therefore it is important to determine the specific pharmacokinetic characteristics for individual drugs in pediatric patients so that appropriate age-specific dosage regimens can be developed and evaluated in clinical trials. This review summarizes the pharmacokinetic parameters of linezolid in pediatric patients and the rationale for the approved dosing recommendations for this population.
Methods. The pharmacokinetics of linezolid in pediatric patients has been evaluated in 4 clinical trials, including >180 patients ranging in age from preterm newborn infants up to 18 years of age. In all of these studies, patients received a single intravenous dose of linezolid. Plasma linezolid concentrations have been determined by validated high performance liquid chromatography (adult studies) or liquid chromatography/mass spectrometry/mass spectrometry (pediatric studies) methods.
Results. The pharmacokinetics of linezolid, especially elimination clearance, is age-dependent. Children younger than 12 years of age have a smaller area under the drug concentration-time curve, a faster clearance and a shorter elimination half-life than adults. Although clearance rates in newborn infants are similar to those in adults, clearance increases rapidly during the first week of life, becoming 2- to 3-fold higher than in adults by the seventh day of life. The clearance of linezolid decreases gradually among young children, becoming similar to adult values by adolescence. The pharmacokinetics of linezolid in children age 12 years and older is not significantly different from that of adults.
Conclusions. Because of the higher clearance and lower area under the drug concentration-time curve, a shorter dosing interval for linezolid is required for children younger than 12 years of age to produce adequate drug exposure against target Gram-positive pathogens.
There can be substantial differences between pediatric and adult patients in the pharmacokinetic parameters of many therapeutic agents, resulting in age-related differences in dosing regimens. 1–3 For example hepatic metabolism can vary considerably as a function of age. Metabolic enzyme systems are incompletely developed at birth, not becoming fully active until ∼6 months of age. 3 As children mature metabolic activity increases substantially, such that the metabolism of certain drugs (e.g. theophylline) in young children is often substantially greater than that observed in adults. 3, 4 In addition there are other developmental and physiologic differences between children and adults that can influence the distribution and elimination of drugs. These include differences in plasma protein levels, extracellular fluid volume, renal blood flow, glomerular filtration rate and tubular secretion. 1–3
Because of these differences knowledge of the specific pharmacokinetic parameters for individual drugs in pediatric patients is required. This allows the agent to be dosed in a manner that ensures the desired therapeutic effect without an undue risk of adverse events. To that end several studies have assessed the pharmacokinetic properties of linezolid in pediatric patients, ranging in age from preterm newborn infants to 18 years. The purpose of this review is to summarize the pharmacokinetic parameters of linezolid in pediatric patients and to discuss the rationale for the approved dosage recommendations for this population.
PHARMACOKINETIC PROPERTIES OF LINEZOLID
Plasma was immediately harvested from the blood samples and frozen at −20°C until analysis. Plasma linezolid concentrations were determined using a validated, high performance liquid chromatographic (HPLC) method at AvTech Laboratories, Kalamazoo, MI. 5 The lower limit of assay quantitation was 0.010 μg/ml. Interday precision during validation was ≤3.9% over the calibration range of 0.010 to 20.0 μg/ml.
After oral administration linezolid is rapidly and completely absorbed (100% bioavailability) with maximum plasma concentration (Cmax) achieved within 1 to 2 h after either single or multiple oral doses. 6, 7 Although the administration of linezolid with food slightly delays the rate of absorption and increases the time to Cmax, the extent of absorption is not significantly affected. 6
The complete bioavailability of linezolid means that similar plasma drug concentrations and area under the drug concentration-time curve (AUC) values are achieved whether the drug is administered orally or intravenously. 8 In adults after administration of single or multiple doses of intravenous linezolid 600 mg, Cmax and AUC values of ∼13 to 15 μg/ml and 80 to 90 μg·h/ml, respectively, are achieved. 9 Linezolid exhibits essentially linear pharmacokinetics, with Cmax and AUC values generally proportional to the dose after single or multiple doses. 7 The concentration-time profile produced by therapeutic dosages of linezolid suggest that steady state concentrations of linezolid are above the highest MIC of 4 μg/ml for target pathogens for 10 to 16 h after oral administration and for 9 to 10 h after intravenous dosing. 10
Data from healthy volunteers suggest that linezolid has good tissue penetration, with a mean distribution into inflammatory blister fluid of 104% of that of plasma concentrations after multiple oral doses of linezolid 600 mg. 11 The mean concentration of linezolid in the inflammatory fluid 12 h after the dose was 4.9 μg/ml, a value above the MIC90 for most target Gram-positive isolates. 11 Linezolid also has demonstrated good penetration into bone, muscle, fat, alveolar cells, lung extracellular lining fluid and cerebrospinal fluid. 10, 12–14 The high degree of tissue penetration is at least partially caused by the low plasma protein binding (31%) of linezolid. 11 The volume of distribution of linezolid at steady state is ∼40 to 50 liters in healthy volunteers. 7
The primary metabolic pathway of linezolid is oxidation of the morpholine ring, resulting in two inactive open ring carboxylic acid derivatives: an aminoethoxyacetic acid metabolite and a hydroxyethylglycine metabolite. 15, 16 The formation of the hydroxyethylglycine metabolite (predominant metabolite) is mediated by a nonenzymatic chemical oxidation mechanism. 15 Linezolid does not appear to be metabolized via cytochrome P-450, nor is it an inducer or inhibitor of this enzyme system. 15, 16
Nonrenal clearance is the primary route of elimination accounting for ∼65% of total clearance. 7, 16 The low renal clearance (40 ml/min) suggests that linezolid undergoes tubular reabsorption. 9 At steady state ∼30% of an administered dose appears in the urine as the parent compound, with ∼50% of the dose as the two major metabolites. 16 Only small amounts of the drug (<10%) are excreted in the feces, primarily in the form of metabolites. 16 The elimination half-life of linezolid ranges from 4 to 6 h in adults after single and multiple doses of the drug and is independent of either the dose or the route of administration. 7, 10
Patient sex and age older than 65 years do not significantly influence the pharmacokinetics of linezolid. 17 Similarly the pharmacokinetics of linezolid is not appreciably altered in patients with either renal or hepatic dysfunction. 18, 19 However, in patients with renal insufficiency, the two major metabolites will accumulate depending on the degree of renal dysfunction. 10 The clinical significance of this accumulation is unknown but does not change the recommendation that the dosage of linezolid need not be altered in patients with renal insufficiency. 9, 10
LINEZOLID PHARMACOKINETICS IN PEDIATRIC PATIENTS
The pharmacokinetics of linezolid in pediatric patients has been evaluated in four clinical trials. These studies included patients ranging in age from preterm newborn infants up to 18 years. These studies are summarized in Table 1 and included >180 children. In all of these studies, patients received a single intravenous dose of linezolid. Plasma was again immediately harvested from the blood samples and frozen at −20°C until analysis. Plasma linezolid concentrations were determined with a validated HPLC system that was coupled with a triple quadrupole mass spectrometer (HPLC/MS/MS) also run at AvTech Laboratories. 20 The lower limit of assay quantitation was 0.020 μg/ml. Interday precision during validation was ≤2.6% over the calibration range of 0.020 to 25.0 μg/ml. This methodology was developed in part to accommodate the need for very small sample volume as a requisite for conducting pharmacokinetic trials in pediatric patients.
In an initial study 58 patients age 3 months to 18 years received a single intravenous dose of linezolid 1.5 mg/kg (n = 44) or 10 mg/kg (n = 14). 21 There was no significant difference in pharmacokinetic values between the two doses; however, there was a significant nonlinear correlation between age and clearance with the greatest clearance values among infants aged younger than 20 months. 21 The difference appeared to be related primarily to age-related differences in nonrenal clearance. 21 Based on the appearance of these age-related pharmacokinetic parameters, data from this and other pediatric pharmacokinetic trials have been stratified according to age (<12 years and 12 to 18 years).
One multicenter study assessed the pharmacokinetics of linezolid in 43 neonates and young infants (≤3 months postnatal age) after a single intravenous dose of linezolid 10 mg/kg. Pediatric patients being treated for a suspected and/or culture-proved bacterial infection and those hospitalized for surgical procedures or other conditions were eligible for the study. Patients were stratified according to postconceptual age at birth (<34 weeks postconception vs. ≥34 weeks postconception) and postnatal age (≤7 days postnatal age vs. >7 days postnatal age).
Pharmacokinetic parameters of linezolid according to gestational and postnatal age are summarized in Table 2. These data suggest that the pharmacokinetics of linezolid in the first week of life varies significantly as a function of postnatal age. The mean clearance for infants <7 days postnatal age was substantially less than that of older infants. The clearance of linezolid was lowest among preterm infants <7 days old; clearance rates were similar to those observed in adult patients. However, the clearance of linezolid increased markedly in the first week of life, regardless of gestational age, such that infants >7 days old had clearance values that were ∼3-fold greater than those of adults. 22 Clearance rates remained substantially elevated through the first 2 to 3 months of life. AUC values were also greater among infants <7 days old compared with older infants, particularly those who were preterm. The volume of distribution of linezolid was not significantly affected by either gestational or postnatal age.
Patients <12 years of age
There were three trials that included patients ranging in age from birth to 12 years. In the initial study pediatric patients 3 months to 17 years of age received a single 30-min infusion of linezolid 10 mg/kg. Patients were stratified into 5 age groups: Group 1 (<12 months); Group 2 (1 to 2 years); Group 3 (3 to 6 years); Group 4 (7 to 12 years); and Group 5 (13 to 17 years). Of the 63 total patients, 36 were in the youngest 3 age groups. Although Cmax values were similar for all age categories, younger patients had lower concentrations at later time points after the infusion, an observation consistent with a higher clearance among the younger patients. Indeed the clearance of linezolid increased in an age-dependent manner, with the youngest age group having weight-adjusted clearance values ∼2.3-fold greater than the oldest age group. Drug exposure was also lower in patients younger than 13 years of age than in older children as evidenced by lower AUC0–∞ values (46 to 73 vs. 90 to 103 μg·h/ml). Similarly the mean elimination half-life generally increased with increased patient age. There was no apparent effect of age on the exposure of patients to the 2 major metabolites, with the possible exception of slightly higher AUC values for the aminoethoxyacetic acid metabolite among the youngest age group. There was also no apparent effect of gender or race with respect to clearance.
Table 2 summarizes the pharmacokinetic parameters of patients 3 months to 11 years of age, derived from pooled data from the three studies that included patients in this age range. The Cmax and steady state volume of distribution (Vss) in these young patients were generally similar to those of adolescent children and adults. However, young children had a smaller AUC, faster clearance and shorter elimination half-life than adolescents and adults.
A population pharmacokinetic analysis was conducted from data obtained in a Phase III, open label, controlled trial that compared oral or intravenous linezolid (10 mg/kg every 8 h) with intravenous vancomycin in children ages 0 to 11 years with suspected or proved resistant Gram-positive bacterial infections. 23, 24 This analysis included data from 195 patients who received at least 6 doses of linezolid. Overall there were no significant differences between routes of administration or age on pharmacokinetic variables. The mean predicted percent time above an MIC value of 4 μg/ml was 54%. These results suggest that a linezolid dose of 10 mg/kg every 8 h in children younger than 12 years of age produces linezolid exposure similar to that observed in adults receiving 600 mg twice daily.
Patients 12 to 18 years of age
There were 3 pharmacokinetic studies that included patients 12 to 18 years of age. In these studies 36 adolescents received a single intravenous dose of linezolid 10 mg/kg (maximum, 600 mg) or 600 mg. Pooled data from these studies are presented in Table 2. 25 Overall the pharmacokinetic parameters of linezolid in adolescents were shown to be similar to those of adult patients, although there was greater interpatient variability among adolescents. The only parameter that was significantly different was Cmax, with adolescents having a higher mean value than adults (16.7 μg/ml vs. 12.5 μg/ml).
One pharmacokinetic study specifically examined the pharmacokinetics of linezolid in adolescents. In this study 18 healthy male and female adolescent subjects age 12 to 17 years received a single 600-mg intravenous dose of linezolid. Compared with adults adolescents had a slightly lower volume of distribution, a higher Cmax and a shorter half-life. However, there was no significant difference between adolescents and adults for the parameters (AUC, clearance) most closely associated with clinical efficacy. Mean AUC values were 91 μg·h/ml for both adolescents and adults, whereas mean clearances were 1.94 and 1.7 ml/min/kg, respectively. These results support a similar dosing schedule for adolescents and adults of 600 mg every 12 h.
Results from studies in pediatric patients have demonstrated that there are age-related differences in the pharmacokinetic parameters of linezolid. Children <12 years of age have a smaller AUC, a faster clearance and a shorter elimination half-life than adults. Newborn infants have clearance values similar to those of adults. However, clearance increases rather markedly during the first week of life, to values 2- to 3-fold in excess of those observed in older children and adults. The clearance of linezolid declines gradually in young children, becoming similar to that of adults by adolescence. After the age of 12 years, the pharmacokinetic parameters for linezolid are not significantly different from those of adults.
The age-related changes in linezolid pharmacokinetics have implications for the appropriate dosing of the drug. These findings support the need for a shorter dosing interval in infants and young children to provide adequate drug exposure. In particular more frequent administration will increase the AUC and plasma trough concentrations. This is important because the AUC:MIC ratio and the time above the MIC are important determinants of linezolid efficacy against Gram-positive pathogens. 26
The recommended dosing guidelines for linezolid according to age are summarized in Table 3. For most indications children <12 years of age should receive linezolid 10 mg/kg every 8 h. 9 The only exception to this is the treatment of uncomplicated skin and skin structure infections, for which the every 8 h schedule is recommended only for children <5 years of age. 9 Because of the lower systemic clearance values and higher AUC values in preterm infants <7 days old, a dosing regimen of 10 mg/kg every 12 h should be initiated for these neonates. 9 However, a 10-mg/kg every 8 h regimen should be considered for those with inadequate clinical response. In addition the dosage should be changed to 10 mg/kg every 8 h for all neonates by the seventh day of life. 9 On the basis of the similarity of their pharmacokinetic profile to that of adults, adolescents should receive the same dosage regimen (600 mg every 12 h) as adults for most indications. 9 These dosage recommendations are supported by efficacy and safety data described elsewhere in this supplement.
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