JAC Advance Access published online on February 13, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn038
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Original research |
Optimized dosage and frequency of cefozopran for patients with febrile neutropenia based on population pharmacokinetic and pharmacodynamic analysis
1 Department of Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan 2 Department of Microbiology, Kyoto Prefectural Institute of Public Health and Environment, Kyoto, Japan 3 Department of Clinical Pharmacotherapy, Hiroshima University Graduate School, Hiroshima, Japan 4 Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan 5 Department of Clinical Molecular Cytogenetics and Laboratory Medicine, Kyoto Prefectural University of Medicine Graduate School of Medical Sciences, Kyoto, Japan
* Correspondence address. Department of Haematology and Oncology, Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kawaramachi-Hirokoji, Kamigyo-ku, 602-8566 Kyoto, Japan. Tel: +81-75-251-5740; Fax: +81-75-251-5743; E-mail: nomuken{at}koto.kpu-m.ac.jp
Received 3 September 2007; returned 3 December 2007; revised 23 November 2007; accepted 10 January 2008
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Abstract |
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Objectives: To establish a cefozopran (a fourth-generation cephem) population pharmacokinetic model using patient data and use it to explore alternative dosage regimens that could optimize the currently used dosing regimen to achieve higher likelihood of pharmacodynamic exposure against pathogenic bacteria.
Methods: We conducted a prospective clinical trial of cefozopran for haematological patients with febrile neutropenia (FN). Twenty-two patients (30 episodes) were selected to receive intravenous cefozopran every 8 h on a daily basis. We gathered concentration data and performed the NONMEM program. The Monte Carlo simulation was performed to assess the pharmacodynamic exposure based on the population pharmacokinetics and MIC.
Results: The NONMEM program demonstrated that a two-compartment model provided a best fit for the data, that is, CL of 4.62 (L/h), V1 of 10.3 (L), Q of 4.47 (L/h), and V2 of 4.48 (L). On the basis of the Japanese national surveillance findings for Pseudomonas aeruginosa, methicillin-sensitive Staphylococcus aureus, coagulase-negative Staphylococcus, viridans group streptococci, Escherichia coli and Klebsiella pneumoniae, Monte Carlo simulation data showed that probability of target attainmentT>MIC = 70% is 67% to 97% for dosing every 8 h, and 48% to 88% for dosing every 12 h. For the patients in whom the efficacy of cefozopran could be evaluated, 17 of 22 patients (77.2%) survived the episode of FN without requiring further antibacterial treatment.
Conclusions: Our study proved that Monte Carlo simulation based on population pharmacokinetics can determine optimized dosage and method. The optimal regimen for this cephem was found to be three times daily.
Key Words: Monte Carlo simulation , haematological malignancies , NONMEM program , Pseudomonas aeruginosa , methicillin-sensitive Staphylococcus aureus
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Introduction |
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According to the guidelines for febrile neutropenia (FN), empirical antibiotic therapy, including a carbapenem or fourth-generation cephem, should be administered promptly to all neutropenic patients at the onset of fever, because the progression of infection is rapid.1 Gram-positive bacteria now account for up to 70% of the microbiologically documented infections. In contrast, Gram-negative bacterial infections are still among the most important causes of mortality during neutropenia in patients with haematological malignancies,2,3 especially when related to Pseudomonas aeruginosa.4
Owing to its anti-P. aeruginosa activity, cefozopran (a fourth-generation cephem) is used as an antibiotic agent for the empirical treatment of bacterial infections in FN patients.5–7 However, when it was first approved by the regulatory authorities in Japan, its recommended dose and administration method was only 2 g/day (1 g every 12 h) because of its impact on healthcare costs, and up to 4 g/day considered only for critically ill patients. Although haematologists have expressed doubts about the efficacy of such a method and dosage, there is no pharmacological or clinical evidence pertaining to the effectiveness of varying the number of doses per day for neutropenic patients.
As antibacterial activity is time-dependent, the time that drug concentrations remain above MIC (T > MIC) is the main determinant for their efficacy.8 This means multiple infusions may help to prevent therapeutic failure and the spread of resistance, as may also be the case when borderline or intermediately susceptible pathogens are involved. Although continuous infusion may be theoretically beneficial,9–13 continuous infusion is not realistic for all patients and the peak concentration may actually be below the mutant prevention concentration (MPC).14
To determine T > MIC, the pharmacokinetic parameters and MICs of the organisms infecting the patient are first determined. However, these are very difficult to identify in a clinical setting, where aggressive blood sampling to assess pharmacokinetic parameters may be problematic for certain patients. We therefore chose a population approach15 for our study and performed a population pharmacokinetic analysis of 22 patients treated with 8 hourly intravenous infusion of cefozopran (2 g, 1 g, 1 g, every 8 h). We used the NONMEM program to determine whether an every 8 h intermittent infusion therapy can ensure the maintenance of a therapeutic concentration in plasma.
The Monte Carlo simulation has been proposed as a clinically practicable method to evaluate the probability of experimental dosage regimens attaining pre-specified pharmacodynamic targets against specific pathogens. By using a probability density function to generate random concentration values, thousands of single-point estimates can be made and their probabilities plotted to examine the entire range of possible drug exposures.16–19 The Monte Carlo simulations should be based on population pharmacokinetic parameters and the data of population MIC frequency distribution of bacteria isolated from FN patients. However, as causal bacteria are difficult to isolate from FN patients (up to 15%),20,21 we substituted the national surveillance data for MIC frequency distribution of P. aeruginosa, methicillin- susceptible Staphylococcus aureus (MSSA), coagulase-negative staphylococci (CoNS), viridans group streptococci, Escherichia coli and Klebsiella pneumoniae.
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Materials and methods |
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Patients
All consecutive patients with haematological malignancies treated at the Hospital of Kyoto Prefectural University of Medicine between April and December 2006 were enrolled in our study. The protocol, including the form for written informed consent for this study, was approved by the Institutional Review Board of Kyoto Prefectural University of Medicine (No. C-163). The purpose, methods and potential adverse outcomes of this study were explained to each patient, after which written informed consent was obtained. All the clinical study procedures were performed in accordance with the Declaration of Helsinki. Patients were eligible for empirical monotherapy with cefozopran if they had neutropenia (<500 cells/mm3, or a count of <1000 cells/mm3 with a predicted decrease to <500 cells/mm3) and a body temperature >38.5°C on one occasion or >38°C on two occasions. Patients were not eligible if they were <16 years old, pregnant or lactating, epileptic, allergic to β-lactams, or had moderate-to-severe hepatic or renal diseases (aspartate aminotransferase and alanine aminotransferase more than five times the upper normal limit; total bilirubin >2.5 mg/dL; creatinine clearance estimated with the Cockcroft–Gault method <50 mL/min).22 Demographic data (age, weight, height, CLCr and underlying diseases) were collected upon enrolment in the study.
Cefozopran 4 g/day (intravenous infusion, 2 g, 1 g, 1 g, every 8 h) was planned to be administered for all patients as it is the maximum dosage permitted by Japanese regulations. We administered 2 g at least once a day, because we aimed to obtain both more time above MIC and peak/MIC, because for the 1 g every 6 h protocol, the peak concentration is low and may not reach the MPC. The pharmacokinetic data derived from these patients were used to develop models of different dosing regimens. We made two protocol models: 2 g, 1 g, 1 g, every 8 h administration and 1 g, 1 g, 2 g, 10:00 am, 16:00 pm, 22:00 pm administration. In view of nursing workload and patients' distress, the latter is thought to be more suitable for patients. However, we selected 2 g, 1 g, 1 g, every 8 h administration in this study, because there is no previous report to prove that time above MIC is identical for these two protocols.
In view of the good stability of cefozopran in solution, 1–2 g cefozopran dissolved in 100 mL saline was infused for 1 h every 8 h. If defervescence was detected and/or cefozopran-susceptible bacteria were isolated from sterile sites after 3–5 days, cefozopran therapy was continued. If, in contrast, no defervescence was detected, the second-line therapy with carbapenem and antifungal agents were started. Each patient's condition was assessed daily with a clinical evaluation and a complete blood count and chemical analysis, which included determination of serum creatinine levels, until the antibiotic treatment was discontinued. Blood for cultures was drawn at the start of drug administration twice a day. The clinical treatment team decided the management of these patients including the need for ancillary investigations, modification of antibiotics, or treatment with antiviral or antifungal medications. Patients could be withdrawn from the study at the discretion of the treatment team if they showed haemodynamic instability. Cefozopran was also discontinued at the discretion of the treatment team. Episodes of FN were categorized as microbiologically documented, clinically documented or as fever of unknown origin, as described elsewhere.23
The total concentrations of cefozopran in plasma were determined with ion-paired HPLC.24 A plasma sample of 150 µL was added to 450 µL of distilled water and transferred to an ultrafiltration device (Nanosep 10K; Pall Corporation, Northborough, MA, USA). The device was then placed in a centrifuge, and 20 µL of the filtrated solution was injected onto a chromatograph. Chromatography was carried out with a reversed-phase column (Symmetry C18; Waters Corporation, Milford, MA, USA) at room temperature and an ultraviolet absorbance detector at 235 nm. Acetonitrile-buffer solution containing 15 mM heptane sulphonic acid (pH 3.2; 45:955) was used for the mobile phase at a flow rate of 1 mL/min. The lower limit of detection was 0.5 mg/L, and the coefficients of variation were within 7%.
The published guidelines for the evaluation of new anti-infective drugs in the treatment of febrile episodes in patients with neutropenia were used as the basis for defining the endpoint assessment of therapeutic outcome.1,25 ‘Excellent’ response was defined as the eradication within 3 days of all symptoms, signs and microbiological evidence of infection that could be attributed to the study regimen. ‘Good’ response was defined as the eradication of all symptoms within 7 days. ‘Poor’ was defined as no improvement in the infection or worsening of the infection while the patient was receiving the initial study regimen and need for the addition of any antibacterial drug. Patients with neutrophil counts that did not become <500 cells/mm3 or with documented fungal or viral infections and those who concurrently received antibiotics other than the study drugs were not included in the evaluation.
Population pharmacokinetic model
A population pharmacokinetic analysis was performed using the NONMEM program (version V; Globomax LLC, Hanover, MD, USA). All plasma concentration data (24 samples from 6 patients after 2 g dose and 64 samples from another 16 patients after 1 g dose) were concurrently fitted to a standard two-compartment model because cefozopran has a linear pharmacokinetics from 0.1 to 2 g.26 Results of fitting the one- and two-compartment models suggested that the two-compartment model more accurately described the data available. The fixed-effects parameters in the two-compartment model were clearance (CL), volume of distribution of the central compartment (V1), inter-compartmental (central–peripheral) clearance (Q2), and volume of distribution of the peripheral compartment (V2). In the basic model, the inter-individual variability was modelled exponentially by the following equation:
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i is the fixed-effects parameter for the ith subject, the mean value of the fixed-effects parameter for the population, and 
a random inter-individual variable that is normally distributed with mean 0 and variance 
2. The residual variability was modelled with the proportional error model |
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ij is a random intra-individual error that is normally distributed with mean 0 and variance 
2. PREDPP subroutines ADVAN3 and TRANS4 and the first-order approximation method were used for the NONMEM analysis. Pharmacokinetic model validation
To evaluate the predictive performance of the population parameters, we also obtained, by using the POSTHOC option in the NONMEM software package, individual Bayesian estimates of CL and V of each of the antibiotics administered to the patients. The pharmacokinetic parameters derived for this study were evaluated by determining their distribution against the linear regression of the predicted versus the observed concentrations in plasma.
Pharmacodynamic analysis using Monte Carlo simulation
A 5000 subject Monte Carlo simulation was conducted to estimate the pharmacodynamic exposure, T > MIC in plasma, for each bacterium–regimen combination. Three different cefozopran regimens were selected: 4 g/day (2 g, 2 g, every 12 h, 1 h infusions), 4 g/day (2 g, 1 g, 1 g, every 8 h, 1 h infusions), and 4 g/day (1 g, 1 g, 2 g, 10:00 am, 16:00 pm, 22:00 pm, 1 h infusions). The total drug concentration was employed because the protein binding of cefozopran was only 8%.26 The following process was iterated from 1st to 5000th subject using Crystal Ball 2000 (Decisioneering, Inc., Denver, CO, USA) using a macro program. A set of fixed-effect parameters (CL, V1, Q2 and V2) was randomly generated as i = * exp() for each mean estimate () and inter-individual variance () of the final population pharmacokinetic model. The drug concentration (48 h after the start of the infusion) versus time curve was created by using the fixed-effect parameters. Subsequently, a different value for MIC was generated by random sampling from the bacterium population with the customary distribution. The time point at which the drug concentration coincided with the MIC value was determined, and the duration for which the drug concentration remained at the MIC was eventually calculated as the cumulative percentage of the dosing interval. The probability of target attainment (PTA) was determined as the fraction that achieved at least 10, 20, 30, 40, 50, 60, 70, 80 and 90% T > MIC of 5000 estimates. As for T > MIC itself, as 60% to 70% is most commonly considered necessary for a near-maximal bactericidal effect, PTAT >MIC=70% was adopted as our standard index.
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Description of episodes of FN
Forty-two episodes (36 cases) were enrolled in our study and three FN cases were rejected because they were being treated with meropenem, cefpirome sulphate or cefepime by the attending physician. Two patients were treated with both cefozopran and clindamycin because of suspected anabolic infection (gingival swelling). Another two patients were proved to have fungal infection after administration of cefozopran, and one case was diagnosed with tumour fever by the clinical treatment team. Neutrophil counts did not drop below 500 cells/mm3 in three patients and one extremely elderly case was treated with three administrations of cefozopran (1 g, 1 g, 1 g, every 8 h). Finally, one case was found not to have haematological malignancy (the first diagnosis was lymphoma and the final diagnosis was mesothelioma), and two cases could not be evaluated with the efficacy analysis because of anaphylaxis reaction and elevation of creatinine.
Thus, 30 episodes (22 cases) were assessed in this study, with 5 (16%) microbiologically documented and the others fevers of unknown origin. No cases of breakthrough bacteraemia with either the same or a different organism occurred during the study.
Patients showed a relatively high percentage of successful recovery from FN (83%) with a median duration of fever of 5 days. Deaths were attributed to extended-spectrum β-lactamase (ESBL)-producing E. coli septic shock (Case 4) and culture-negative septic shock (Case 7) (Table 1). MICs of cefozopran and cefepime for ESBL-producing E. coli were 4.0 and 2.0 mg/L, respectively. We performed phenotypic confirmatory testing by testing the isolate against ceftazidime and cefotaxime alone and in combination with clavulanic acid (cefotaxime/clavulanic acid and ceftazidime/clavulanic acid, respectively).26 Enterobacter cloacae (MIC > 64 mg/L) and P. aeruginosa (MIC = 0.5 mg/L) were detected in Cases 5 and 8, respectively. The former obtained good outcome and the latter obtained excellent outcome.
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Population pharmacokinetics
Biphasic elimination was demonstrated by plotting the plasma concentration profile (Figure 1). The mean estimated population pharmacokinetic parameters and their 95% CIs are summarized in Table 2. Q was finally evaluated as a fixed value without inter-individual variability because was <0.0001 in the basic model. The pharmacokinetic parameters were estimated with the Bayesian method using the NONMEM program. Figure 2 shows the diagnostic plots of the weighted residual versus predicted concentration, the population predicted versus observed concentration, and the individual predicted versus observed concentration. These plots indicate that the model developed for this study lacks bias and provides good characterization of the cefozopran pharmacokinetics of the patients.
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Simulated T > MIC and PTA
For the simulation results, individual pharmacokinetic parameters CL and Vd as well as the MIC value were generated for each of the 5000 virtual patients. To assess the expected PTA against the main causal bacteria, P. aeruginosa, MSSA, CoNS, viridans group streptococci, E. coli and K. pneumoniae, the Monte Carlo simulation using the data of the Japanese national surveillance (Table 3) demonstrated that PTAT>MIC=70% was 48% to 88% for 2 g every 12 h, 67% to 97% for 2 g, 1 g, 1 g every 8 h, and 67% to 97% for 4 g/day (1 g, 1 g, 2 g, 10:00 am, 16:00 pm, 22:00 pm) for all the bacteria investigated (Figures 3–5).
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For E. coli (MIC50
0.06 mg/L and MIC90 0.12 mg/L), K. pneumoniae (MIC50 0.06 mg/L and MIC90 0.12 mg/L), viridans group streptococci (MIC50 0.12 mg/L and MIC90 0.25 mg/L), CoNS (MIC50 2 mg/L and MIC90 16 mg/L), MSSA (MIC50 1 mg/L and MIC90 2 mg/L) and P. aeruginosa (MIC50 2 mg/L and MIC90 16 mg/L), three doses per day attained PTAT>MIC=70% values 8% higher for E. coli and K. pneumoniae, 11% higher for viridans group streptococci, 18% higher for CoNS, 22% higher for MSSA and 19% higher for P. aeruginosa than the value attained with two administrations, respectively. |
Discussion |
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Recent pharmacokinetic–pharmacodynamic developments have been outstanding. As the antibacterial activity of cephems has been proved to be based on time above MIC,8 the Monte Carlo simulation has been substituted for measurement of trough levels to predict acute clinical outcome.19,27 However, for a Monte Carlo simulation, population pharmacokinetic parameters are essential. Some clinical reports based on a population pharmacokinetic analysis for healthy subjects have been published.17,27 However, there have been no reports of population pharmacokinetic approaches using sampled patients' data. Ours is thus the first population pharmacokinetic analysis of FN patients. It has been long believed that there is no difference between healthy subjects and patients in terms of pharmacokinetic parameters.28 However, recent studies have demonstrated that there are differences between pharmacokinetic parameters for patients and healthy volunteers.29 The clearance parameters in infected patients show a tendency to increase and drug washout time is rapid, especially because most patients with haematological malignancy are relatively young and have normal renal function, so that population pharmacokinetic analysis is essential for accurate prediction. It was easy to obtain pharmacokinetic parameters statistically for 22 patients (88 samples) in a short time. Population pharmacokinetic parameters can also be derived from Phase III studies, but this method needs much labour and time and is very costly.
The results of Monte Carlo simulations are considered to provide investigators with reasonable confidence as to which dosage regimens have the highest probability of positive outcome and thus warrant further development in a large clinical trial. Because the difference in PTAT>MIC=70% between three and two administrations per day was as large as 20%, it provided pharmacokinetic–pharmacodynamic evidence that three times daily dosing of cefozopran for FN patients is more useful. In fact, Case 5 obtained cure in 7 days by three times daily administration of cefozopran, in spite of the high MIC of the isolated E. cloacae (>64 mg/L). The efficacy of three times daily administration of cefozopran in our study proved to be 83%. Compared with the utility of twice-daily administration,30,31 we proved that administration three times daily has better efficacy, even though our study population was small and was not randomized. In the treatment of FN patients, different times of administration tend to affect clinical outcome directly, because FN patients need more time above MIC than immunocompetent patients. It has been reported that three times daily administration of another fourth-generation cephem, cefepime, also has better efficacy than twice-daily administration.20,21,32,33 Our study thus proved the clinical pharmacological hypothesis that drug concentrations remaining above the MIC is the main determinant for efficacy.
PTAT>MIC=70% was almost identical for the two protocols for 4 g/day (2 g, 2 g, 1 g, every 8 h; 1 g, 1 g, 2 g, 10:00 am, 16:00 pm, 22:00 pm) for MSSA, CoNS, viridans group streptococci, E. coli, P. aeruginosa and K. pneumoniae. Thus, clinical outcomes for treatment with 4 g/day (1 g, 1 g, 2 g, 10:00 am, 16:00 pm, 22:00 pm) are thought to be same. Considering the workload for nurses and patients' distress, 4 g/day (1 g, 1 g, 2 g, 10:00 am, 16:00 pm, 22:00 pm) administration is also recommended.
In conclusion, three times daily infusion of 4 g (2 g, 1 g, 1 g) cefozopran is the most appropriate administration protocol for Japanese patients. Because the pharmacokinetic parameters have been determined, physicians should, for the prediction of clinical outcome, perform a Monte Carlo simulation with population MIC frequency distribution at their institution. Our study proved the utility of Monte Carlo simulation and established the optimal drug dose and administration method for FN.
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This study was supported by a grant from the Japan Research Foundation for Clinical Pharmacology.
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None to declare.
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Acknowledgements |
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We especially thank the Heads of Nurses, Naomi Nakamura and Kyoko Tachikawa and the nurses in wards B8 and D8.
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References |
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