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Levofloxacin Pharmacokinetics in Children

From Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, New Jersey (S. Chien, Dr Natarajan, Dr Maldonado, Dr Noel); University of Arkansas for Medical Sciences and the Arkansas Children's Hospital PPRU, Little Rock, Arkansas (Dr Wells); Rainbow Babies and Children's Hospital PPRU, Cleveland, Ohio (Dr Blumer); University of Missouri–Kansas City and the Children's Mercy Hospitals and Clinics PPRU, Kansas City, Missouri (Dr Kearns); Children's Hospital and Health Center and the UCSD/Children's Hospital PPRU, San Diego, California (Dr Bradley); Louisiana State University Health Sciences Center–Shreveport and the Louisiana State University Health Sciences Center–Shreveport PPRU, Shreveport, Louisiana (Dr Bocchini); and University of Medicine and Dentistry of New Jersey, Newark, New Jersey (Dr Noel).

Address for reprints: Shuchean Chien, MS, Johnson & Johnson Pharmaceutical Research & Development, LLC, 920 Route 202 South, PO Box 300, Raritan, NJ 08869-0602.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Levofloxacin is a broad-spectrum fluoroquinolone antibiotic with activity against many pathogens that cause bacterial infections in children, including penicillin-resistant pneumococci. To provide dosing guidance for children, 3 single-dose, multicenter pharmacokinetic studies were conducted in 85 children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16 years. Each child received a single 7-mg/kg dose of levofloxacin (not to exceed 500 mg) intravenously or orally. Plasma and urine samples were collected through 24 hours after dose. Pharmacokinetic parameters were estimated and compared among the 5 age groups and to previously collected adult data. Levofloxacin absorption (as indicated by C_max and t_max) and distribution in children are not age dependent and are comparable to those in adults. Levofloxacin elimination (reflected by t and clearance), however, is age dependent. Children younger than 5 years of age clear levofloxacin nearly twice as fast (intravenous dose, 0.32±0.08 L/h/kg; oral dose, 0.28±0.05 L/h/kg) as adults and, as a result, have the total systemic exposure (area under the plasma drug concentration-time curve) approximately one half that of adults. The levofloxacin area under the plasma drug concentration-time curve (dose normalized) in children receiving a single dose of the oral liquid formulation is comparable to that in children receiving the intravenous formulation. To provide compatible levofloxacin exposures associated with clinical effectiveness and safety in adults, children 5 years need a daily dose of 10 mg/kg, whereas children 6 months to <5 years should receive 10 mg/kg every 12 hours.

Key Words: Levofloxacin • pediatrics • pharmacokinetics

To examine the potential age dependence in the pharmacokinetics of levofloxacin, 3 single-dose pharmacokinetic studies were conducted in children from the ages of 6 months to 16 years following either an intravenous or oral dose as a liquid formulation. Pharmacokinetic data were compared among 5 age groups (6 months to <2 years, 2 to <5 years, 5 to <10 years,10 to <12 years, and 12 to 16 years) and to previous data from adults receiving a single 500-mg dose of levofloxacin (7 mg/kg for adults with average body weight of 70 kg) that had demonstrated clinical effectiveness and safety.

	MATERIALS AND METHODS

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Study Designs
Three studies were conducted to characterize the pharmacokinetics of levofloxacin in children. Two open-label studies administered a single intravenous (IV) dose, and a third open-label study administered a single oral (PO) dose of a liquid formulation of levofloxacin. Study 1 (IV dosing) was conducted with 20 hospitalized children, aged 6 months to 12 years. Study 2 (IV dosing) involved 24 hospitalized children aged 8 to 16 years. Study 3 (PO dosing) involved 41 children, aged 6 months to 16 years. In all 3 studies, children either had documented or presumed bacterial infections and were receiving concomitant antimicrobial therapy prescribed independently of the study protocol. Children were housed in an appropriate hospital unit for at least 12 hours following administration of the study medication. Subject eligibility was restricted to those with no evidence of clinically significant abnormal hematology, serum chemistry (including assessment of albumin concentration, hepatic and renal function), or urinalysis laboratory values. Subjects were excluded if they were taking other quinolones or any other concomitant medication that might interfere with the interpretation of the study results (eg, loop diuretics, probenecid, cimetidine, or drugs or natural products known to induce or inhibit hepatic microsomal enzymes).

Enrollment in each of these 3 studies was stratified by age. Children in study 1 (n = 20; 6 months to <2 years, 2 to <5 years, 5 to <12 years) and study 2 (n = 24; 8 to <10 years, 10 to <12 years, and 12 to 16 years) received a single 7-mg/kg dose of levofloxacin (final concentration 5 mg/mL; diluted in 5% dextrose and water D₅W) infused intravenously at a constant rate over 1 hour using a syringe pump with microbore tubing. Childreninstudy3(n = 41; 6 months to <2years, 2 to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16 years) received a single 7-mg/kg oral dose of levofloxacin suspension. Levofloxacin PO doses were administered with an age-appropriate volume of water (90-120 mL at 4 °C) or clear liquids to ensure complete delivery of the dose to the stomach. Subjects did not have solid foods for at least 2 hours before and 2 hours after dosing. Clear liquids, such as apple juice, were permitted until 1 hour before and 1 hour after dose. All study medication (both IV and PO formulations) was derived from a single lot of levofloxacin so as to minimize variability in drug potency between patients in a given study. In all 3 pediatric investigations, the total dose of levofloxacin did not exceed 500 mg.

In each study, blood samples (2.0 mL each) were obtained at various time points during a 24-hour postdose period through an indwelling venous cannula placed in an extremity. For the intravenous study, blood samples were collected from an extremity contralateral to the one used for levofloxacin infusion. When possible, 36- and 48-hour postdose blood samples were also collected. Urine samples were collected by spontaneous voiding from subjects who were toilet trained and who could reliably provide quantitative collections. Blood samples were collected into glass tubes containing sodium heparin, mixed by inversion, and were centrifuged at 2500 rpm for 10 minutes at room temperature. Plasma was removed by manual aspiration, placed into a screw-capped polypropylene vial, and frozen at –20 °C until assay. Urine samples were collected, the volume and pH determined, and a 20-mL aliquot transferred to a polypropylene bottle and frozen at –20 °C until assay. Both plasma and urine samples were analyzed within 6 months from collection.

The total concentration of levofloxacin in plasma or in urine was determined by a validated high-performance liquid chromatography (HPLC) method.¹¹ The method had a range of linearity from 0.08 to 5.12 µg/mL, and the inter- and intra-assay precision values (expressed as percent coefficient of variation) were consistently below 10% for all concentrations in the range of linearity. The limit of quantification for the assay was determined to be 82 ng/mL. The accuracy of the method was reflected by measured concentrations of the quality control samples that were consistently within ±10% of the target concentrations. Stability of samples (defined as <10% loss of initial concentration) was previously verified through 2 years when maintained at –20 °C. The assay was selective, and there was no assay interference by the presence of concomitant medications.

Tolerability was evaluated by assessment of adverse events, clinical laboratory tests, vital signs, and physical examinations. Complete physical examinations were performed within 48 hours before and after dosing. Vital signs were obtained immediately before study drug administration and at the end of the study. Clinical laboratory tests included hemoglobin, hematocrit, red blood cell, white blood cell, and platelet counts; serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, alkaline phosphatase, total protein, total bilirubin, blood urea nitrogen, serum albumin, serum creatinine, sodium, potassium, and chloride levels; and gross and microscopic urinalyses.

Subjects were recruited at 5 study sites: University of Arkansas for Medical Sciences and the Arkansas Children's Hospital PPRU, Little Rock, Arkansas; Rainbow Babies and Children's Hospital PPRU, Cleveland, Ohio; University of Missouri–Kansas City and the Children's Mercy Hospitals and Clinics PPRU, Kansas City, Missouri; Children's Hospital and Health Center and the UCSD/Children's Hospital PPRU, San Diego, California; and Louisiana State University Health Sciences Center–Shreveport and the Louisiana State University Health Sciences Center–Shreveport PPRU, Shreveport, Louisiana. Laboratory analysis of plasma and urine samples was conducted at Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, New Jersey. Independent institutional review boards at each study site reviewed the study protocol. Informed consent was obtained from the parent or guardian and assent from subjects age 7 years before the initiation of any study-related procedures.

Pharmacokinetic Analysis
Levofloxacin plasma concentration-time data were analyzed by standard noncompartmental methods.¹² Pharmacokinetic parameters characterizing the absorption (C_max, t_max), distribution (Vd), elimination (t and clearance [CL]), and total systemic exposure (area under the plasma drug concentration-time curve [AUC]) of levofloxacin in children were estimated. The apparent C_max and t_max values were estimated by visual inspection of the plasma drug concentration-time data for each subject. The AUC was obtained by the linear trapezoidal rule up to the final measurable concentration (Cp_last) and was extrapolated to infinity (AUC_0-), calculated as AUC_0-last +Cp_last/k_el, where k_el is the terminal elimination rate constant (ie, the slope of the plasma concentration-time profile at the terminal log-linear phase, as determined by least squares linear regression), and AUC_0-last is the AUC from 0 hours to the time corresponding to Cp_last. Apparent total body clearance (CL for IV and CL/F for PO) was determined as dose/AUC_0-. The terminal plasma elimination half-life (t) was calculated as 0.693/k_el and the apparent volume of distribution (Vd) as CL/k_el. The renal clearance (CL_R) was calculated by the equation Ae/AUC, where Ae is the cumulative amount of drug excreted within the sampling interval, and AUC is the AUC of the drug in plasma extrapolated to the end of the urine collection period. For comparison, pharmacokinetic data from adult male volunteers (aged 18-53 years) were included that were derived from previously published methods.¹³

Statistical Analysis
Pharmacokinetics of levofloxacin in children was compared among the 5 age groups (6 months to <2 years, 2 to <5 years, 5 to <10 years, 10 to <12 years, and 12 to 16 years) and to data collected from separate studies in which healthy fasting adults received a single 500-mg levofloxacin dose (approximately equivalent to 7 mg/kg) in either the IV (20-40 years, n = 23; 1-hour IV infusion) or PO liquid formulation (19-55 years, n = 36). The pharmacokinetic parameters of interest for the statistical analysis were C_max, CL, and Vd. Because AUC is correlated with CL to a constant value (ie, CL = dose/AUC), a separate statistical analysis for AUC was not performed. The analysis of variance models was fit to the data with one of the pharmacokinetic parameters as the dependent variable and the age group as the categorical predictor. The age group effect was tested at the 5% level of significance. If the age group effect was found to be significant, then the pairwise comparisons for age groups were tested at a level of significance of = 0.003 for each pairwise test (overall 5% level of significance). Statistics were performed using SAS Version 6.12 (SAS Institute, Cary, NC).

	RESULTS

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Patient Population
Eighty-five children (20, 24, and 41 in studies 1, 2, and 3, respectively) ranging from 6 months to 16 years of age were enrolled and completed the study, and thus they were evaluated for tolerability. Eighty subjects had sufficient concentration-time data to accurately determine pharmacokinetic parameters and consequently were included in the pharmacokinetic evaluation. The 5 subjects not included in the pharmacokinetic evaluation included 1 subject from study 1 (withdrew from the study immediately after dose and before any pharmacokinetic sample was collected), 3 from study 2 (pharmacokinetic sample labels fell off during shipment), and 1 from study 3 (vomited immediately after receiving study drug and was withdrawn from the study). Demographics and baseline characteristics of the 80 pharmacokinetically evaluable children are provided in Table I. In general, levofloxacin was well tolerated, and no severe adverse events were reported by any of the participants during the study period.

Pharmacokinetics
The mean plasma levofloxacin concentration-time profiles for each age group receiving either the IV or PO dose are illustrated in Figures 1 and 2, respectively. Regardless of the route of drug administration, the profiles for infants (6 months to 2 years old) and younger children (2 to 5 years old) were found to be nearly superimposable, as were the profiles between children 10 to 12 years old and children 12 to 16 years old. When comparing levofloxacin plasma concentration profiles resulting from the PO and IV administrations, each of the age groups showed similar profiles after the initial time points (ie, from 0 to 2 hours).

View larger version (18K): [in this window] [in a new window]   Figure 1. Mean values of levofloxacin plasma concentration versus time profiles in children and adults receiving a single intravenous (IV) dose of levofloxacin (children, 7 mg/kg; adults, 500 mg). Each symbol indicates the mean plasma concentration for subjects in the corresponding age group.

View larger version (18K): [in this window] [in a new window]   Figure 2. Mean values of levofloxacin plasma concentration versus time profiles in children and adults receiving a single oral (PO) dose of levofloxacin (children, 7 mg/kg; adults, 500 mg). Each symbol indicates data for subjects in the corresponding age group.

The levofloxacin pharmacokinetic parameters after IV and PO dosing for each of the 5 pediatric age groups and for adults are shown in Table II. The statistical test results from intergroup comparison using ANOVA are presented in Tables III and IV. No age-dependent difference was observed for C_max between the 5 age groups and adults (P = .194). When Vd was normalized by body weight, the pairwise comparisons were found not to be significantly different, except the comparison between children <2 years of age and adults (P = .0002). In contrast, levofloxacin apparent total body clearance (CL or CL/F, normalized by body weight) was shown to vary as a consequence of age until approximately 10 years of age (Tables II, III, IV).

Safety
No subjects experienced a drug-related adverse event that was considered serious or life threatening, and no tendon- or joint-related adverse events were observed. All of the reported treatment-emergent adverse events were considered by the investigator to be mild or moderate in severity. There was 1 serious adverse event of wound dehiscence, but this was judged by the investigator to not be drug related. Proteinuria, indicated by positive dipstick, occurred in 2 patients but was resolved spontaneously upon repeat evaluation. There were no clinically significant changes in laboratory values from the predose to postdose evaluations.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results of these single-dose studies indicate that, with the exception of CL or CL/F, the pharmacokinetics of levofloxacin did not appear to vary as a consequence of age between 6 months and 16 years (Table II). The apparent total body clearance of levofloxacin was inversely associated with age (Table II, Figure 3). Specifically, clearance consistently decreased with age until 10 years of age (IV, 0.35 ± 0.13 to 0.19 ± 0.05 L/h·kg; PO, 0.31 ± 0.13 to 0.20 ± 0.06 L/h·kg; Table II), where it stabilized to values slightly higher than those previously observed in adults (IV, 0.15 ± 0.02 L/h·kg; PO, 0.14 ± 0.03 L/h·kg; Table II). When an inverse first-order nonlinear regression curve fit was applied to the apparent total body clearance versus age profiles, it was observed that the most significant change occurred during the first 1 to 2 years of age; the decrease slowed down afterward and stabilized at 10 years of age (Figure 3). This phenomenon may be explained by the fact that levofloxacin is minimally metabolized and primarily excreted renally as an unchanged drug. In view of the fact that the developmental profile for the acquisition of the glomerular filtration rate reflects the attainment of maturity over the first 1 to 2 years of age, ¹⁴ the pattern for age dependence in levofloxacin apparent clearance found in the present study (Figure 3) was expected. Children younger than 5 years of age cleared levofloxacin nearly twice as fast (IV, 0.32 ± 0.08 L/h·kg; PO, 0.28 ± 0.05 L/h·kg; Table II) as adults and, as a result, had a total systemic exposure (AUC) approximately one half that of adults (Table II).

View larger version (14K): [in this window] [in a new window]   Figure 3. Apparent total body clearance versus age profiles in children and adults receiving a single dose of levofloxacin (children, 7 mg/kg; adults, 500 mg). Values are shown for subjects after an intravenous (filled circles) or oral dose (open circles).

The results from the current investigation also demonstrate that the apparent bioavailability of levofloxacin in children was virtually 100% (Table II; mean AUC ratios between the PO and IV administrations were 120%, 114%, 99%, 94%, and 101% for 6 months to <2 years, 2 to <5 years, 5 to <10 years,10 to <12 years, and 12 to 16 years, respectively) and was compatible with the absolute bioavailability (99%-103%) observed from the adults receiving the same oral liquid formulation in a crossover bioavailability study (Johnson & Johnson Pharmaceutical Research & Development, LLC; data on file).

Levofloxacin exhibits concentration-dependent bactericidal activity, and clinical outcomes are related to the ratios of AUC/MIC or C_max/MIC. To identify a dosing regimen that provides comparable levofloxacin exposures between adults and children, a pharmacokinetic/pharmacodynamic (PK/PD) modeling approach was applied. An optimal dosing regimen can be based on the following criteria: (1) achieving a steady-state C_max and AUC that do not exceed the C_max or AUC that have been shown to be well tolerated by adults, ¹⁵ (2) achieving a steady-state C_max/MIC that has been shown to be effective in treating adults, ¹⁶ and (3) approximating 70% to 130% the steady-state AUC/MIC that has been shown to be associated with effectiveness in adults. Data collected from the 3 studies indicate that a 2-compartment pharmacokinetic model with constant input and first-order output (parameters listed in Table V), which passed the goodness-of-fit and the Akaike and Schwartz model selection criteria, is most appropriate for dosing regimen simulation for children. On the basis of this PK/PD model, children of older age (5 years) would require a 10-mg/kg body weight dose once daily, whereas children of younger age (6 months to <5 years) should receive a 10-mg/kg dose every 12 hours. Predicted steady-state levofloxacin exposures in children under these dosing regimens are presented in Table VI. Safety, efficacy, and population pharmacokinetics of these dosing regimens are currently being evaluated in children 6 months to 16 years of age. Population pharmacokinetic analysis will provide important confirmation, particularly because the sample size for each group in the current study was small. It is also important to recognize that these recommendations should not be extrapolated to infants younger than 6 months of age, a population that has not yet been studied.

The study results demonstrate that an age-dependent difference in total body clearance of levofloxacin occurs at a magnitude sufficient to warrant age-specific dosing regimens. Extrapolation of dosing in children based on the defined pharmacokinetics of levofloxacin in adults may result in insufficient drug exposure in children, especially for those younger than 5 years of age.

	FOOTNOTES

 
This work was funded by Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, New Jersey. Dr Kearns and Shuchean Chien are members of the ACCP.

DOI: 10.1177/0091270004271944

Submitted for publication March 19, 2004; Revised version accepted October 7, 2004.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Chien, S. Articles by Noel, G. J. Search for Related Content PubMed PubMed Citation Articles by Chien, S. Articles by Noel, G. J. Social Bookmarking                   What's this?