JAC Advance Access originally published online on May 24, 2007
Journal of Antimicrobial Chemotherapy 2007 60(1):100-106; doi:10.1093/jac/dkm125
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Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit
1 Pharmacy Department, University Hospital of Heidelberg, Im Neuenheimer Feld 670, D-69120 Heidelberg, Germany 2 Department of Hygiene and Medical Microbiology, University Hospital of Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany 3 Department of Surgery, University Hospital of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany 4 Department of Anesthesiology, University Hospital of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany
* Corresponding author. Tel: +49-6221-56-38118; Fax: +49-6221-56-5413; E-mail: hang.nguyen{at}med.uni-heidelberg.de
Received 12 December 2006; returned 8 February 2007; revised 21 March 2007; accepted 5 April 2007
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Abstract |
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Background: Co-morbidity, medical and surgical interventions often cause alterations to drug plasma concentrations and pharmacokinetic parameters in critically ill patients. In the present study, we investigated parameters influencing plasma caspofungin concentrations in patients of a surgical intensive care unit (SICU).
Methods: In a monocentre open study, caspofungin trough concentrations (C24) were determined for a group of SICU patients. A linear-mixed model was then used to assess factors influencing caspofungin plasma concentrations.
Results: A total of 40 SICU patients were enrolled. Age and body weight ranged from 22 to 76 years and 47 to 108 kg, respectively. All participants received a caspofungin loading dose of 70 mg and a maintenance dose of 50 mg/day. The median duration of therapy was 10 days. Caspofungin C24 in SICU patients varied more than those determined for healthy subjects reported in previous studies (0.52–4.08 µg/mL versus 1.12–1.78 µg/mL). According to our model, caspofungin C24 were predicted to be significantly higher in patients with body weight <75 kg (P = 0.019) and patients with albumin concentration >23.6 g/L (P = 0.030).
Conclusions: Our results show that body weight and albumin concentration influence caspofungin C24 in SICU patients and should therefore be considered prognostic factors.
Keywords: fungal , mycology , drug monitoring
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Introduction |
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Pharmacokinetic parameters and drug plasma concentrations in critically ill patients are often different from those in healthy subjects.1–3 This is due to physiological and physiopathological alterations caused by trauma, sepsis, septic shock and surgery.4–6 Haemodynamic response and vital support therapy are also known to influence pharmacokinetic parameters.2,7,8 For example, wide variabilities in aminoglycoside pharmacokinetic parameters such as clearance, volume of distribution and half-lives have been reported for critically ill trauma patients.4,9 Furthermore, the pharmacokinetic parameters of some pharmaceuticals have been shown to be influenced by haemodialysis: examples include meropenem and fluconazole where elimination half-lives were increased and reduced, respectively.10,11
Surgical intensive care unit (SICU) patients are susceptible to fungal infections. Caspofungin is the first echinocandin approved for the treatment of invasive fungal infections caused by Candida spp. and Aspergillus spp. Because it is generally well tolerated and appears to have limited interaction with other drugs, caspofungin is potentially an important agent in the treatment of invasive fungal infections in critically ill patients. The standard dose of caspofungin is a loading dose of 70 mg followed by 50 mg daily, administered intravenously over 1 h. Caspofungin pharmacokinetics and plasma concentrations in healthy subjects have been reported and findings from these studies have shown that both body weight and sex influence caspofungin plasma concentrations.12,13 Moreover, for patients with liver dysfunction the pharmacokinetic parameters of a drug are often altered. Accordingly, manufacturer's recommendations suggest reduced doses of caspofungin for patients suffering from liver dysfunction.13,14 The aim of the current study was to investigate the influence of certain factors on caspofungin plasma concentrations in a group of severely ill SICU patients.
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Materials and methods |
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Study design
The current work was a single-centre study conducted in the Department of Anaesthesiology of the University Hospital of Heidelberg, Germany. The study protocol was approved by the Competent Authority (BfArM, Bonn, Germany) and the Ethics Committee of the University Hospital, Heidelberg, Germany. Written informed consent was obtained for each patient.
Demographics and medical characteristics
Potential prognostic factors included demographic data such as age, sex, body weight and medical characteristics including sequential organ assessment failure (SOFA) scores, acute physiology and chronic health evaluation (APACHE)-II scores, organ support therapy, concomitant medication, vital support therapy and various physiological parameters. Organ support therapy included haemodialysis (mainly continuous veno-venous haemodiafiltration) and molecular adsorbent recirculating systems (MARS). Where patients were receiving combined therapy, precedence was given to investigate the effect of those drugs considered to be interactive with caspofungin: these were immunosuppressants, steroids and rifampicin.13,15,16
Inclusion and exclusion criteria
Adult patients (age > 18) with either suspected or proven invasive fungal infections caused by Candida spp. or Aspergillus spp. and being treated with caspofungin as regular medication were enrolled in this study. History of hypersensitivity or severe intolerance to caspofungin or other constituents resulted in patients being excluded from the study.
Caspofungin was given as an intravenous infusion for 60 min. The loading dose was 70 mg followed by 50 mg/day. In cases of liver dysfunction or body weight of >80 kg, dose adjustments were optional and made under the direction of the treating physician according to summary product characteristics (SPC).13 Special warnings and interactions stated within the SPC were heeded and any decisions regarding dose adjustment (maximum daily dose: 70 mg) or duration of therapy were made by the treating physician. Patients were monitored for the occurrence of other side effects (liver enzyme, serum creatinine and potassium level). The routine monitoring of patients was not influenced or interrupted by the current study.
Caspofungin acetate and internal standard were provided by Merck Research Laboratories (West Point, PA, USA). Plasma caspofungin concentrations were determined using a slightly modified version of the combined solid-phase extraction/HPLC method described by Schwartz et al.17 The range of the calibration curve was 100–1000 ng/mL and the limit of quantification was 100 ng/mL. Validation procedures were conducted for caspofungin concentrations of 300, 500 and 700 ng/mL according to FDA guidelines. The coefficients of variation for inter-day precision for these concentrations were 5.9%, 8.8% and 9.7%, and for intra-day precision they were 3.3%, 6.1% and 4.5%, respectively. Coefficients of variation for accuracy for the same caspofungin concentrations ranged from 2.4% to 8.2%. Quality controls of three different caspofungin concentrations were included in every analysis and each concentration was analysed in duplicate.18
Blood samples for the determination of caspofungin trough plasma concentrations (C24) were taken directly before the next scheduled dose. Arterial blood samples were collected into ethylenediaminetetraacetic acid-containing tubes and immediately centrifuged for 10 min. Plasma was transferred to polypropylene storage tubes and stored at –70°C until required for analysis.
A linear-mixed model (PROC MIXED, SAS® 9.1, SAS Institute GmbH, Heidelberg, Germany) was used to assess the influence of potential prognostic factors on caspofungin plasma concentrations. All error terms were modelled as variance components. Covariates included both demographic data (e.g. sex, age, body weight) and variables such as SOFA score, APACHE-II score, haemodialysis, MARS, albumin concentration, use of vasopressors, immunosuppressants, steroids and rifampicin. The selection of covariates was conducted by stepwise deletion and those variables with a P value <0.1 were subsequently entered into the final model. Factors remaining in the final model were further analysed using simple models (simple regression) to stabilize the predictions of the mixed model (multiple regression).
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Study population
Forty patients were enrolled and 38 patients were evaluated (2 drop-outs), 15 female and 23 male patients of SICU. The population consisted of 13 cancer patients, 12 solid organ recipients (7 liver and 5 kidney), 5 trauma patients, 3 patients suffering from chronic pancreatitis and 5 patients with intra-abdominal infection. Caspofungin therapy was administered to patients in cases of proven or suspected fungal infections. Two patients were given caspofungin for antifungal prophylaxis following liver transplantation. For all patients, cultures of blood, urine, bronchial alveolar lavage, sputum, central venous catheter or drainage liquid were examined for the presence of yeasts and moulds. Most yeast and mould species isolated from the samples were Candida albicans (32.4%), followed by Candida glabrata (20.6%), Aspergillus fumigatus (14.7%) and other Candida non-albicans species. All patients were treated with caspofungin according to the manufacturer's standard dose regimen. The median duration of therapy was 10 days. The total number of caspofungin plasma samples measured was 334 and the median number of samples per patient was 9. Patient characteristics and supportive therapies selected for the model development are summarized in Tables 1 and 2.
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Caspofungin C24 in SICU patients
The results of caspofungin C24 in SICU patients are summarized in Figure 1. Caspofungin concentrations in SICU patients were found to be slightly higher (mean: 2.16 µg/mL) than those for healthy subjects previously reported by Stone et al.33 (mean: 1.41 µg/mL). Furthermore, the range of caspofungin concentrations determined for our SICU patients (day 2: 0.52–4.08 µg/mL) was greater than that reported by Stone. et al.33 (day 2: 1.12–1.78 µg/mL). However, for the duration of treatment, 75% of our SICU patients were found to have plasma caspofungin concentrations within the range 1.0–3.0 µg/mL, i.e. were above 1 µg/mL which was defined as the target concentration because this concentration exceeds the MIC90 for most clinically relevant Candida species.19,20 Ninety-five percent of our patients were found to have caspofungin C24 within the range 0.8–4.5 µg/mL. Nevertheless, caspofungin plasma concentrations for a number of patients were found to be below the target concentration for either part, or, in some cases, almost the whole of the duration of therapy (9 days, n = 1; 7 days, n = 1; 4 days, n = 3; 3 days, n = 1; 2 days, n = 2; 1 day, n = 9). Of the 17 patients with caspofungin C24 < 1 µg/mL, 10 had body weights >75 kg.
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Statistical model
Prognostic factors were selected for our linear-mixed model using the stepwise deletion technique. The only drug–drug interactions considered in the model were those of caspofungin with tacrolimus and methylprednisolone. For other drugs, the number of therapy days was too few to allow inclusion. The sequence of the stepwise deletion for the covariates considered for inclusion in the mixed model was as follows: sex, APACHE-II score, concomitant use of tacrolimus, age, use of vasopressors and SOFA score. Following the deletion process, albumin concentration, body weight, haemodialysis and co-administration of methylprednisolone were found to have final P values <0.1 and were therefore allowed to remain in the final model.
According to our mixed model, if any influence of body weight >75 kg, albumin concentration >23.6 g/L, methylprednisolone and haemodialysis are ignored, mean caspofungin C24 are predicted to be 2.04 µg/mL. Two covariates were predicted to influence caspofungin C24. Foremost amongst these was body weight: for patients with body weight in excess of 75 kg, caspofungin C24 could be expected to decrease by 0.58 µg/mL (P = 0.019), relative to patients with body weight <75 kg. For patients with albumin concentrations >23.6 g/L, our model predicted a significant 0.24 µg/mL (P = 0.03) rise in caspofungin C24. Haemodialysis and methylprednisolone were predicted not to have a statistically significant influence on caspofungin C24 (P values >0.05).
According to the simple models, concomitant treatment with methylprednisolone could be expected to exert the most significant effect by increasing C24 by 0.46 µg/mL (P = 0.006). Other factors predicted to exert significant effects were body weight >75 kg (P = 0.008) and albumin concentration >23.6 g/L (P = 0.027), which were estimated to decrease and increase caspofungin C24 by 0.6 and 0.25 µg/mL, respectively. No significant correlation was found between haemodialysis and caspofungin C24. A summary of these findings is given in Table 3.
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Discussion |
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The pharmacokinetic parameters of anti-infective drugs are known to be influenced by various patient-specific parameters as well as concomitant supportive therapy.2 It is therefore important that as new drugs become available, an insight is gained into the effect of patient-specific parameters on pharmacokinetics. This is particularly important where patients are suffering from multiple diseases and infections. One such group are those patients being treated in SICUs for whom pharmacokinetics are known to be different from those of healthy subjects.2,9,21 Few studies have addressed pharmacokinetic parameters in SICU patients. This is surprising because it is well documented that drug distribution and metabolism in this patient group can be severely impaired.2,21–26 Data concerning the influence of some factors such as hepatic or renal insufficiency, obesity or drug–drug interactions and/or drug metabolism are often available.27–32 However, the extrapolation of these data to patients with multiorgan failure or those under complex life supportive therapy is unacceptable. Moreover, the influence of supportive therapy has been shown to affect the pharmacokinetic parameters of some drugs. Examples include fluconazole and aminoglycosides in which significant inter-patient pharmacokinetic parameter variability in ICU patients resulted from renal dysfunction, gastrointestinal surgery and the effect of haemodynamic response to sepsis and/or vital support therapy.8,9,21
In the present study, caspofungin C24 were determined for patients of a SICU in order to investigate any relationships between specific covariates and caspofungin plasma concentrations. On day 1 of therapy, caspofungin C24 were found to be greater in SICU patients than levels previously reported for healthy subjects.33 Increased drug plasma concentrations in the SICU patients monitored in the current study could have resulted from decreased drug distribution and/or drug elimination. Common causes of increased drug plasma concentrations include alterations to protein binding, lack of organ perfusion and/or organ dysfunction.2 These physiological changes are common in SICU patients and could be responsible for the observed increased caspofungin C24 in our SICU patients. However, Stone et al. reported caspofungin C24 in healthy subjects only for days 1 and 14 of therapy.33 It was not therefore possible to compare caspofungin C24 in our SICU patients to those previously reported for healthy subjects.
Stone et al. reported a loading-dose effect for caspofungin in healthy subjects. Following the administration of a loading dose, caspofungin C24 in healthy subjects were reported to peak after 1 day and then fall but remain above the target concentration for the duration of therapy.33 In contrast, this loading-dose effect was not observed for SICU patients monitored in the current study. In all cases, the loading-dose peak reported by Stone et al. was absent and although caspofungin C24 in most of the monitored patients remained above the target concentration, for some patients, caspofungin C24 failed to reach the target concentration (Figure 1). These differences in caspofungin plasma concentrations between healthy subjects and SICU patients are not surprising because, as noted above, a number of studies have reported similar effects for other drugs. In most cases, these differences in plasma concentrations have been ascribed to the influence of disease and supportive therapy in SICU patients.34,35 We suggest that these findings are the result of a combination of the influence of various diseases, supportive therapy and various surgical and medical interventions.
In a number of our SICU patients, caspofungin C24 were found to be lower than the target concentration of 1 µg/mL for the first 11 days of therapy (Figure 1). Body weight is known to influence the PK of caspofungin in healthy subjects: higher body weight generally results in lower caspofungin C24.13 Caspofungin C24 <1 µg/mL may therefore have been expected in those SICU patients with higher body weights (i.e. >80 kg). However, our results suggest that for SICU patients, factors other than body weight are also likely to contribute to a decrease in caspofungin plasma concentrations. According to reports in the literature, a number of factors can serve to decrease drug plasma concentrations in critically ill patients. These include increased metabolic capacity and elimination caused by fluid resuscitation, application of vasopressors/inotropes, hypodynamic shock and an increase in the volume of distribution.2,36–38
Caspofungin C24 ranges were found to be relatively wide in our SICU patients (Figure 1: day 1: 0.52–4.08 µg/mL) when compared with those for healthy subjects reported by Stone et al. (day 1: 1.12–1.78 µg/mL). The wide concentration ranges associated with our data are primarily due to high inter- and intra-individual variability resulting from the many clinical factors influencing our patient group. Surgical and medical interventions appear to have been the primary influence on intra-patient caspofungin C24 in our patient group.
In terms of demographic and clinical status, our SICU patient group were extremely heterogenous. As such, multiple interactions between potentially influencing factors had to be considered in the statistical analysis of our data and subsequent model development. Accordingly, as many potentially influencing factors as practicable were included in the development of our linear-mixed model.
According to the manufacturer's SPC, caspofungin concentrations are affected by body weight. Both the simple and mixed models support this and indicate that body weight does have a significant influence on caspofungin C24. According to our models, the caspofungin maintenance dose should be increased for SICU patients with body weight >75 kg. However, it should be noted that the body weight of critically ill patients often falls during their treatment in a ICU.2 Any decision regarding dose adjustment for caspofungin should therefore take this into account.
Previous investigation of healthy subjects by Stone et al. showed that caspofungin is extensively bound to albumin (
97%).39 ICU patients often develop hypoalbuminaemia resulting from liver disease, extensive bleeding, burns and/or renal impairment.6,40,41 However, blood albumin concentrations usually remain high enough to ensure that the unbound fraction of administered drugs remains relatively constant.42 When compared with healthy individuals, albumin concentrations in our SICU patients were decreased by ~50% to ~60%. Although these differences may be considered quite large, we did not expect the equilibrium between unbound and bound caspofungin to have been shifted to any great extent. However, according to our simple and mixed models, hypoalbuminaemia was one of the factors predicted to increase caspofungin C24 with respect to healthy individuals. One possible explanation is that decreased colloid osmotic pressure (caused by hypoalbuminaemia) resulted in a decrease in the distribution of caspofungin into tissues. However, other factors that may have influenced caspofungin plasma concentrations include capillary permeability, third spacing and multiple organ dysfunctions.2,36,37,43,44
Reports in the literature indicate that renal insufficiency and haemodialysis do not necessitate dose adjustment for caspofungin because plasma concentrations do not change significantly in patients with renal insufficiency and the extensive binding of caspofungin to albumin precludes its removal by haemodialysis.13,45 In accordance with these findings, both simple and mixed models predicted no statistically significant influence of haemodialysis on caspofungin C24.
To date, drug–drug interactions have only been reported for caspofungin with enzyme inducers such as rifampicin and dexamethasone as well as immunosuppressants like cyclosporin A and tacrolimus.13,15,16,45 In the current study, rifampicin, cyclosporin A and mycophenolate mofetil were excluded from statistical analysis because of too few days of concomitant therapy for our SICU group. The mixed model did however suggest that for our SICU patient group, caspofungin C24 were not affected by tacrolimus. These findings were in agreement with previous studies.15 According to the linear-mixed model, methylprednisolone was predicted to not significantly influence caspofungin C24. However, the P value associated with this variable was low (P = 0.057) suggesting that further investigation using a larger cohort of patients may be necessary. This is also supported by the predictions of the simple model where concomitant treatment of methylprednisolone was predicted to have an influence on caspofungin C24 (P = 0.006).
In conclusion, compared with healthy subjects, caspofungin C24 for the SICU patients monitored in the current study were increased. Body weight and hypoalbuminaemia were found to be prognostic factors responsible for these increased caspofungin concentrations. Additionally, within our SICU population, caspofungin C24 were found to vary greatly suggesting requirement for close monitoring of plasma concentrations of this drug in SICU patients. Accordingly, dose adjustment should be necessary in cases where caspofungin C24 fall below the target concentration of 1 µg/mL. However, the 1 µg/mL target concentration should only be regarded as a prognostic factor if there is a correlation to outcome. For caspofungin, this has yet to be evaluated.46,47
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T. H. N. has served as a speaker for MSD Sharp & Dohme and received an unrestricted travel grant for the attendance and presentation of a poster at the Forty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy 2004 from MSD Sharp & Dohme. M. A. W., H. K. G. and T. H.-T. have served as speakers for MSD Sharp & Dohme.
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Acknowledgements |
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We are grateful to Gerd Mikus for his contribution and Steffen Witte for his help in performing the statistical analysis. This study was supported by an independent grant from MSD Sharp & Dohme, Germany.
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References |
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