Objective. Quinolones are used ever increasingly in pediatrics, although officially they are still contraindicated. Lack of evidence of arthropathic effects in human offspring favors their use, but little is known about the pharmacokinetics of oral or parenteral ciprofloxacin in children, especially those without cystic fibrosis.
Design. We studied 16 non-cystic fibrosis patients ranging in age from 0.3 to 7.1 years to whom the new suspension formulation of ciprofloxacin (10 mg/kg body weight) was given orally three times daily. Single-dose and steady-state pharmacokinetic parameters were elucidated.
Results. Ciprofloxacin was rapidly absorbed. The maximum plasma concentrations, with the means varying from 1.7 to 3.6 mg/L, were reached within 1 hour, almost regardless of whether single-dose administration or steady state. The mean oral clearance was lower in children <6 years of age than in those ≥6 years. Terminal half-life values, with the means varying only between 4.2 and 5.1, suggest that dosing recommendations based on body weight are pertinent, although caution should be exercised in small infants. No arthropathic or other adverse events attributable to ciprofloxacin suspension were observed.
Conclusion. A dose of the suspension form of ciprofloxacin of 10 mg/kg body weight given orally three times daily seems appropriate in children, provided the drug is clearly indicated.
- CF =
- cystic fibrosis
In adults, ciprofloxacin has been an effective and rather safe antimicrobial for which parenteral and oral forms are available. Its spectrum covers a number of clinically important pathogens, especially Gram-negative bacteria including Pseudomonas aeruginosa, against which very few oral drugs are available. Hence, ciprofloxacin became widely used soon after registration in many countries in the 1980s.
However, ciprofloxacin has not been licensed for general pediatric use because, as with other fluoroquinolones, it has the potential to cause cartilage erosion in the weight-bearing joints in some species of young animals.1 2 Despite this, ciprofloxacin has sometimes been used in children with specific problems,3 4 mostly for patients with cystic fibrosis (CF).3 5-9 The general experience is that ciprofloxacin is safe and effective in children also; side effects have been infrequent (5%–15%), mild, and reversible. Arthropathy has not been observed even with the most sensitive detection methods, including routine ultrasound screening and nuclear magnetic resonance.1 4 8-10
Pharmacokinetic data on ciprofloxacin in children are scant. Three reports deal with different dosage regimens,4 6 7 and one study addresses the question of metabolite kinetics,5 but no information exists on oral suspension of ciprofloxacin.
Using a new formulation, we investigated the single-dose and steady-state pharmacokinetics of ciprofloxacin suspension and its metabolites in children not suffering from CF.
PATIENTS AND METHODS
The study was performed at the Helsinki University Central Hospital, Hospital for Children and Adolescents, Finland, in 1994–1995. This open-label clinical trial comprised 16 patients, aged 0.3 to 7.1 years, who fulfilled the entry criteria for the study. The children were suffering from urinary tract infections, chronic otitis media, endocarditis, or were salmonella carriers; ciprofloxacin was given because there had been no response to conventional therapies. The study was conducted in accordance with the principles of the act of Helsinki, and written consent was obtained for each patient from their legal guardians. All good clinical practice rules were followed, and the trial was approved by the ethical committee of the university hospital.
Ciprofloxacin oral suspension (Bayer AG, Wuppertal, Germany) was supplied in separate bottles having 7 g of ciprofloxacin microcapsules and 140 mL of oily vehicle. Storage was at room temperature. Before use of the drug, the pharmacist prepared the doses required; 1 mL of suspension contained 50 mg of ciprofloxacin betaine. When ready to use, the suspension was stored at room temperature for a maximum of 14 days. Used bottles were returned to the manufacturer.
Dosing was based on the patient's body weight checked on the day of ciprofloxacin institution. At least seven doses of 10 mg/kg body weight of the suspension were administered in a three-times-daily dosing regimen. Instead of the twice-daily dosing, common in adults, we selected the three-times-daily regimen because it seemed reasonable for children in whom high concentration peaks should perhaps be avoided.4 Each dose was ingested at least 1 hour apart from milk or yogurt intake under fasting conditions, but juice or water was given ad libitum. Drugs, such as antacids, and vitamin preparations, including multivalent cations (magnesium, aluminum, calcium, zinc, etc), were avoided; other medication was allowed but kept at a minimum. Irrespective of the body weight, the maximum daily dose of ciprofloxacin did not exceed 1500 mg (adult maximum dose).
An intravenous line was placed in a peripheral vein by a pediatric anesthetist and kept open with heparin. After the initial dose, 1 to 2 mL of blood was collected in heparinized tubes at 0 (predose), 0.5, 1, 2, 4, 6, and 8 hours after dosing, and again at steady-state (after the last dose), when additional 12- and 24-hour samples were obtained to describe the terminal phase of the plasma concentration versus time course. The total blood loss was <32 mL. The separated plasma was transferred into polypropylene tubes and frozen immediately at −70°C before analysis.
Assays were performed by Bayer AG at the Institute of Clinical Pharmacology, Wuppertal, Germany. A validated high-performance liquid chromatographic method with fluorescence detection was used to measure the concentration of ciprofloxacin and desethylene-ciprofloxacin (metabolite M1) in plasma.11 The limit of quantification was 10 μg/L for ciprofloxacin and 2.5 μg/L for M1. For the quantification of sulfo-ciprofloxacin (metabolite M2) and oxo-ciprofloxacin (metabolite M3), postcolumn photothermal derivatization was used before fluorescence detection of their decomposition products. The limits of quantification were 10 μg/L for both compounds.
Appropriate quality control samples were co-analyzed with the study samples. With this measure, interday precision of <7.2%, <5.3%, <6.7% and <8.2% and accuracy of 99%, 97%, 100% and 101% were established for ciprofloxacin, M1, M2, and M3 throughout the working range of the assays.
Plasma protein binding at different concentrations of ciprofloxacin was determined in duplicate ex vivo using a membrane filtration method. Pooled plasma samples from 3 patients were deproteinated by ultrafiltration (Centricon) centrifugation, and the unbound drug was measured in the ultrafiltrate.
Pharmacokinetic parameters were determined using noncompartmental methods as described previously.12 The following parameters were calculated: the maximum plasma concentrations after the first dose (Cmax) and in the steady-state (Cmax,ss) with the time to Cmax (Tmax); the area under the concentration curve from 0 to infinity (AUC = AUC0-∞); the area under the curve for the dosing interval at steady-state (AUCτ,ss, AUC0–8,ss); the apparent oral clearance (CL/f, CL/f,ss); and the terminal half-life (t1/2). Where applicable, the corresponding dose and body weight-normalized parameters were given. Linearity of the pharmacokinetics was estimated by calculating the AUC0–8,ss/AUC ratios for ciprofloxacin (Ra). The percentage of unbound drug (fu) was calculated from this formula: fu = 100 × concentration in ultrafiltrate/concentration in plasma (%), whereas, for accumulation of the drug, the following equation was used: Ra = AUCτ,ss/AUC in which Ra = the accumulation ratio, indicating accumulation of ciprofloxacin due to nonlinear behavior at steady state. The data obtained were compared with those from other studies presenting data for ciprofloxacin kinetics in pediatric patients.4-6
Before entering the study, all patients were examined by one of the investigators (pediatricians). Drug administration was witnessed by an assigned study representative. The patients remained in the hospital ward throughout the study period.
An individual questionnaire on adverse events due to ciprofloxacin was filled in each case. Possible relation of all potential reactions to the drug had to be assessed using a grading from none to not assessable. Special attention was paid to find any symptoms or signs suggesting acute arthropathy. Tests on hematology (hemoglobin, hematocrit, platelet, erythrocyte, and leucocyte counts, differential) and blood chemistry (serum creatinine, alkaline phosphatase, and aspartate, and alanine aminotransferases) were obtained routinely before, during, and after the treatment with ciprofloxacin, which lasted 7 to 10 days in most cases.
The demographic data of the study population, including doses administered to each patient, are presented in Table1. Sixteen children (7 boys and 9 girls) aged 4 months to 7 years were eligible for pharmacokinetic evaluation. Hematology was checked from 2 additional patients, who were not eligible for pharmacokinetics because serum (instead of plasma) samples had been taken.
The children were assigned to one of four groups according to age: <1 year (n = 4); 1 year (n = 3); 2 to 5 years (n = 6); and ≥6 years (n = 3). The mean age (range) was 0.6 (0.3–0.8), 1.3 (1.1–1.6), 4.6 (2.5–5.3), and 6.8 (6.3–7.1) years for the four age groups, respectively. The corresponding mean body weights were 7.6 (6.4–8.8), 11.0 (10.7–11.4), 15.9 (11.9–20.0), and 22.5 (20.7–23.8) kg. One female patient (aged 3 years) did not participate in the second round (steady-state phase) of sampling because of major problems in maintaining the intravenous line.
The pharmacokinetic data obtained are summarized in Table2. Absorption was rapid, although the mean Tmax was shorter in the steady-state (Tmax = 1 hour for all groups) than after the first dose, when a slightly greater variability was observed (range, 1–4 hours). The mean AUCs were in comparable ranges after the first (10.8–7.7 mg h/L) and the last dose (10.3–6.8 mg h/L). AUC for infants was marginally greater than for the other three age groups.
The mean maximum plasma concentration (Cmax) was achieved within 1 hour after dosing, regardless of whether the initial dose or steady-state (Figure), except for the infant group in whom a slightly greater concentration was measured after 2 hours (1.8 mg/L) than 1 hour (1.3 mg/L). Overall, there were no major differences between individuals, and the maximum mean concentrations varied only between 1.7 and 3.6 mg/L.
The Cmax values tended to be higher under steady-state conditions (2.0–3.6 mg/L) than after the first dose (2.0–2.7 mg/L). In the steady-state, there was a biphasic decline in plasma concentrations, characterized by an initial distribution phase during which Cmax was reduced by approximately 50% in the first hour (Figure)1. The dominant half-life (t1/2) after a single dose of ciprofloxacin was 1.9–2.6 hours (geometric mean 2.3 [1.3] hours); this value increased to 4.2 to 5.1 hours at steady-state, indicating that there were no major differences between the four age groups (Table 2). After the first dose, the biphasic decline was not fully detectable because sampling was possible for only 8 hours. For infants, the plasma concentration time curve can be better described as monophasic. AUC and AUCτ,ss produced by the three-times-daily dosing did not differ significantly in the four age groups (Table 3). No distinct distribution phase was observed after oral administration.
The mean oral clearance tended to be lower in the children younger than 6 years (16.4–18.3 mL min/kg) than in the oldest age group (24.4 mL min/kg). The Ra ratios indicate that there was no significant accumulation of the drug in the steady-state.
All metabolites identified in pharmacokinetic studies in adults were detectable in our series also. The concentration time courses of the metabolites were parallel to those described for the parent drug. Although the formation of phase 1 metabolites (M1 and M3) did not differ significantly in the four age groups, there was a slight trend toward increased AUC and Cmax with decreasing age for M2, suggesting that phase 2 metabolite formation may be more pronounced in infants.
Plasma Protein Binding
Ex vivo data indicated that approximately 33% to 40% of oral ciprofloxacin was bound to plasma proteins. There was no major age-related change in protein binding, except for the infants in whom the unbound fraction was slightly lower: fu (%) 33.7 and 33.3 in two measurements versus 37.7 and 39.4, respectively, at 2 to 5 years of age. Overall, the values found were higher than in adults, 27%.5 The measurements revealed that protein binding was concentration-independent in the study population.
No adverse events attributable to ciprofloxacin were documented during the trial, and none of the children were withdrawn from the study except one with insurmountable difficulties with the intravenous line. A slight, always insignificant, increase in the mean counts for eosinophils (approximately from 1.5% to 3%) and lymphocytes (from 55% to 70%), and a slight decrease in the neutrophil count (from 35% to 25%) and total white blood cells (from 11 000 to 7000 per mm3 [11 to 7 × 109/L]) were observed, but there was no reason to assume the changes were specifically caused by ciprofloxacin. The changes were not considered to have any clinical significance. No arthropathy was noticed during or after hospitalization.
Before this series, only one study reported on pharmacokinetics of ciprofloxacin in children without CF.4 Those children received ground tablets. We deem our experience on oral suspension is relevant because ciprofloxacin (and other quinolones) appear to be undergoing increased usage in pediatrics. In 1996 in the United States, no less than 8.4 million prescriptions were written for patients 18 years and younger of whom 12 000 were infants.12a Recently the first quinolone for topical use in children was released.
In general, no acute adverse or untoward events were observed. The suspension was rapidly absorbed, and the plasma concentration time profiles were similar to those observed in healthy adults, who have received a single oral dose of 750 mg,13 and to children with CF, who were given ciprofloxacin 10 mg/kg intravenously twice daily or 15 mg/kg orally twice daily.5 The Figure presents the plasma concentration vs time profiles at steady state for the four different age groups.
The finding of increased elimination of ciprofloxacin at 1 to 5 years of age—as suggested by reduced terminal half-life with the use of ground tablets4—was not evidenced by this study with ciprofloxacin suspension. The terminal half-life (range, 4.2–5.1 hours) in this series was in excellent accordance with the values found in other age groups. Our interpretation is that more frequent dosing is not necessary, if ciprofloxacin suspension is used.
For fluoroquinolones in general, the ratio of the area under the concentration time curve and the minimum inhibitory concentration is likely to be the pharmacokinetic or pharmacodynamic criterion most predictive of clinical outcome.14 15 Based on the steady-state values of AUC0–24, the 8-hour administration of 10 mg/kg body weight in children is comparable, obviously with regard to microbiologic outcome, to doses of 400 mg given intravenously three times daily or 750 mg orally twice daily in adults (Table4).5 13 16
Data on the ciprofloxacin metabolites M1, M2, and M3 have not been available for pediatric patients without CF. In infants and children, the metabolites seem to behave as seen earlier5 13 with a trend toward changed metabolic clearance of oral suspension in infants. In this group, sulfation of ciprofloxacin, formed by phase 2 metabolism, seems to prevail, whereas other metabolites formed by CYP 450 isoenzymes are almost unchanged. Our results agree with the earlier ones17 18 indicating that small infants have a higher capacity for sulfation than do adults. This study somewhat challenges the view that age plays only a minor role in ciprofloxacin dosing.19 Most differences in pharmacokinetic behavior can be expected in early childhood, during the rapid development of organs and changes in physiology, gastric motility, renal function, distribution of body water, etc.20-22
Overall, our results suggest that pharmacokinetics of the ciprofloxacin suspension did not change much in the study population. Consequently, the data do not require changes in the dose recommendation (∼10 mg/kg body weight three times daily), although a better index than body weight would perhaps be preferable. If the benefit outweighs the potential risks (of which we are unaware), pharmacokinetic investigations should be extended to infants younger than 3 months and neonates.
We thank Drs Rolf Kubin, Harald Reinhart, Mats Ögren, and Gertrud Ahr for their technical assistance during the study. Research assistant Sini Kangas contributed to the preparation of the manuscript.
- Received March 25, 1997.
- Accepted August 20, 1997.
Reprint requests to (H.P.) HUCH Hospital for Children and Adolescents, Stenbäckinkatu 11, 00290, Helsinki, Finland.
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- Copyright © 1998 American Academy of Pediatrics