1 School of Pharmacy, University of Southern California, Los Angeles, CA; 2 Laboratory of Applied Pharmacokinetics, 3 USC Adult Cystic Fibrosis Center and 4 Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Received 18 January 2002; returned 18 March 2002; revised 5 June 2002; accepted 3 July 2002
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Abstract |
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Introduction |
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The pharmacokinetics of aminoglycosides administered once daily in CF patients are currently not well described. Several investigators have compared the pharmacokinetics of once-daily with multiple daily dosing of tobramycin in small numbers of patients with CF.69,12,13 However, these investigations have utilized model-independent analysis and thus have not characterized the distribution phase. Preliminary evidence suggests that the pharmacokinetics may be dose dependent.8,14
This study evaluated the pharmacokinetics of once-daily tobramycin administration in adult CF patients admitted for the treatment of an acute pulmonary exacerbation. The specific aim of this project was to compare the distribution and elimination patterns of traditional dosing (3.3 mg/kg q8h) with once-daily dosing (10 mg/kg q24h).
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Materials and methods |
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The pharmacokinetics of once-daily tobramycin in CF patients admitted for an acute pulmonary exacerbation was examined in this prospective, crossover trial. This study was approved by the Institutional Review Board at the University of Southern California. All patients gave written informed consent. Six adult patients were recruited to receive either 3.3 mg/kg every 8 h or a single 10 mg/kg dose of intravenous tobramycin in 100 mL of 5% dextrose in water on the first day. On the second day, the patients were crossed over to receive the alternative dose. The 3.3 mg/kg dose was infused over 30 min and administered every 8 h for 1 day, while the 10 mg/kg dose was administered as a single 60 min infusion. Inclusion criteria for this study were: age >18 years, most recent sputum culture positive for Pseudomonas aeruginosa and admission for treatment of an acute pulmonary exacerbation. Patients were excluded if they were pregnant, attempting to conceive or nursing an infant, had a history of hypersensitivity to an aminoglycoside, or did not have intravenous access at the time of recruitment.
Blood samples
Blood samples (5 mL) were obtained from an indwelling venous catheter prior to administration, at the end of infusion, then at 10, 20, 30, 45, 60, 90, 120, 240 and 450 min post-dose. An additional sample at 720 min was obtained following the administration of the 10 mg/kg dose. The catheter was flushed with 510 mL of 0.9% sodium chloride before and after each blood sample was collected. The first 3 mL of each blood sample was discarded. Each blood sample was immediately placed on ice and allowed to clot. The sample was then centrifuged and the serum harvested. Serum (12 mL) was transferred from each sample and frozen at 70°C until assayed.
Analytical determination of tobramycin concentrations
Serum tobramycin concentrations were determined using a validated fluorescence polarization immunoassay (TDx; Abbott Laboratories, Irving, TX, USA). The lower limit of detection for the assay is 0.1 mg/L. The assay precision was determined by measuring four replicates of six concentrations representing the observed range of concentrations in all patients. The coefficient of variation for concentrations of tobramycin equal to 0.25, 4, 11, 21, 29 and 35 mg/L was 3.5, 3.7, 1.3, 1.2, 1.5 and 3.4%, respectively.
Pharmacokinetic analysis
Standard two-stage pharmacokinetic analysis was performed using ADAPT II (Biomedical Simulations Resource, University of Southern California, Los Angeles, CA, USA).15 Serum concentrations were fitted to one- and two-compartment models (Figure 1) using maximum likelihood analysis. Model discrimination was based on Akaike information criteria. The primary pharmacokinetic parameters obtained from the analysis were the volume of central compartment and peripheral compartments (Vc, Vp), the clearance (CL) and distribution clearance (CLd). The distribution () and elimination (ß) rate constants, and distribution (t
) and elimination (tß) half-lives were also derived using standard equations.
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Descriptive statistics were calculated for each subjects height, weight, age, body surface area, body mass index, predicted creatinine clearance and dose. Differences in pharmacokinetic parameters between the two dosing regimens were assessed by the MannWhitney U-test. A P value <0.05 was considered statistically significant. Correlation analyses were performed to assess the relationship between pharmacokinetic parameters and individual patient covariates.
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Results |
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Discussion |
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The pharmacokinetic parameters found in the present study compare favourably with those from previous investigations (Table 4),8,9,12 with the exception of the study conducted by Vic et al.7 Vic and colleagues published two studies evaluating the pharmacokinetics of amikacin and one comparative trial of multiple versus once-daily dosing of tobramycin in patients with CF.6,7,13 In each of these studies the estimates of the volume of distribution and the interpatient variability are much higher than that previously reported. In addition, the reported tobramycin clearance values for both the q8h and once-daily regimens are much lower than the values found in our study and those reported by previous investigators. In their pharmacokinetic analysis, Vic and colleagues fitted the serum concentration data to a two-compartment model using non-linear least squares regression. One possible explanation for the apparent discrepancy in the pharmacokinetic parameters may be inappropriate weighting of the serum concentration data in the regression analysis.16 One limitation to our study is the small sample size, which may have limited the determination of any statistical significance between the two groups.
Our study is the first to characterize the distribution phase following single daily dosing of an aminoglycoside in patients with CF. In contrast to the results reported by Demczar et al.14 in healthy volunteers, we did not find the distribution phase to be dose dependent. The importance of the distribution phase in the clinical setting pertains to the timing of concentrations necessary to determine the optimal dose. The current practice commonly employed in the clinical setting is to obtain a peak concentration 30 min after a 30 min infusion.8,11 Our data suggest that sampling 30 min after a 30 min infusion of the multiple daily regimen, or 30 min after the once-daily regimen, would give concentrations in the distribution phase. Considering the relatively long distribution half-life of 30 min for both dosing regimens in our study, the distribution phase would be expected to be 94% complete by 2 h (four distribution half-lives). Therefore, use of a one-compartment model would require clinical peak levels to be drawn 2 h after initiation of either a 30 min infusion for multiple daily dosing or a 60 min infusion with once-daily dosing, to ensure completion of the distribution phase. If the peaks were drawn prior to completion of the distribution phase, the pharmacokinetic parameter estimates determined by a one-compartment model would be inaccurate and could lead to incorrect assumptions about the appropriateness of the dosing regimen. As our data show, a two-compartment model more accurately describes the disposition of tobramycin than a one-compartment model, and should ideally, therefore, be used in the therapeutic drug monitoring of these patients. D-optimal sampling design is a method that has been employed to determine the optimal number, and timing, of measurements to maximize the information about the pharmacokinetic parameters to be estimated.15,17 A prospective study comparing the traditional method of monitoring (e.g. one-compartment model applied to a peak obtained 30 min after a 30 min infusion and trough) with the recommended method (e.g. two-compartment model applied to serum concentrations obtained at the D-optimal times) would enable determination of the most precise method of achieving the pharmacodynamic goals of therapy.
The larger aminoglycoside doses prescribed to patients with CF are based on the altered pharmacokinetics (higher clearance and larger volume of distribution) demonstrated in previous studies, allowing for larger total daily doses to achieve higher peak concentrations, followed by rapid elimination prior to the next dose. The reported advantage of once-daily aminoglycoside administration is that a significantly greater number of patients will achieve the pharmacodynamic target of a peak concentration exceeding 10 x MIC.18 Results of a large phase III study of aerosolized tobramycin in patients with CF demonstrated that the MIC50 and MIC90 against P. aeruginosa are 1 and 8 mg/L, respectively.19 Therefore, in order to maximize the pharmacodynamic activity of tobramycin in patients with CF, a peak concentration of 20 mg/L is required to provide the desired peak/MIC ratio of 10 against susceptible isolates (MIC 2 mg/L).20 Our data indicate that a dose of 10 mg/kg/day provides post-distributional phase peak concentrations that achieve the desired goal for susceptible organisms (>20 mg/L) and AUC24 values at the upper end of the desired range (70100 mg·h/L).21
In conclusion, the pharmacokinetics of once-daily tobramycin in patients with CF was best described using a two-compartment model. Our data suggest that distribution is not complete 30 min after a conventional dose or once-daily dose. Thus, clinical analysis using standard peak times may lead to erroneous conclusions about the revised pharmacokinetic parameters and clinical efficacy. Rather, it is recommended that clinicians utilize a two-compartment model with samples obtained immediately after the end of infusion and at trough times for a 3.3 mg/kg q8h dose, and immediately after the end of the infusion and 12 h after the start of the infusion for a 10 mg/kg q24h dose. Samples beyond 12 h will approach the limit of detection for the assay and may therefore preclude estimation of the pharmacokinetic parameters. Alternatively, if a one-compartment model is assumed, the peak concentration should be obtained at least 2 h after initiation of either a 30 min infusion when receiving q8h dosing or a 60 min infusion for once-daily dosing to determine the appropriateness of the dose and facilitate revision of the regimen if necessary.
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Acknowledgements |
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Footnotes |
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References |
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