JAC Advance Access published online on September 13, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm349
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Pharmacokinetics of voriconazole during continuous venovenous haemodiafiltration
1 Department of Internal Medicine 3, Intensive Care Unit 13H1, Medical University Vienna, Vienna, Austria 2 Department of Clinical Pharmacy and Diagnostics, University of Vienna, Vienna, Austria 3 Department of Internal Medicine 1, Division of Infectious Diseases, Medical University Vienna, Vienna, Austria
* Corresponding author. Tel: +43-1-40400-4767; Fax: +43-1-40400-4797; E-mail: valentin.fuhrmann{at}meduniwien.ac.at
Received 12 March 2007; returned 3 June 2007; revised 29 July 2007; accepted 15 August 2007
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Abstract |
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Objectives: Voriconazole is a new triazole antifungal agent that is frequently used in intensive care patients with severe fungal infections. Continuous venovenous haemodiafiltration (CVVHDF) is an important extracorporal renal replacement therapy in critically ill patients suffering from severe infections and multiple organ failure. This study investigates the pharmacokinetics of voriconazole in anuric patients undergoing CVVHDF.
Patients and methods: Pharmacokinetic analysis was performed in nine intensive care patients—one of them with liver cirrhosis—with suspected or proven fungal infection and acute renal failure undergoing CVVHDF who received voriconazole intravenously. The concentration of voriconazole in serum and ultradiafiltrate was determined by HPLC.
Results: Mean peak pre-filter voriconazole concentration in eight patients without cirrhosis was 5.9 ± 2.9 mg/L and mean pre-filter trough level was 1.1 ± 0.3 mg/L. Mean elimination half-life, mean volume of distribution, mean AUC0–12 and mean sieving coefficient were 14.7 ± 6.5 h, 228 ± 42 L, 22.4 ± 3.7 mg·h/L and 0.56 ± 0.16, respectively. The total clearance was 12.9 ± 6.7 L/h and the clearance via CVVHDF was 1.1 ± 0.3 L/h. In the patient with liver cirrhosis, elimination half-life, volume of distribution, AUC0–12 and sieving coefficient were 52 h, 301 L, 19.8 mg·h/L and 0.31, respectively.
Conclusions: Voriconazole should be given without a dosage adaptation in critically ill patients without liver cirrhosis undergoing CVVHDF. However, according to results in one patient, reduction of the maintenance dosing regimen of voriconazole seems to be meaningful in patients with liver cirrhosis.
Key Words: renal replacement therapy , pharmacokinetics , intensive care unit , antimycotic agents
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Introduction |
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Voriconazole is a new triazole antifungal agent that shows excellent in vitro and in vivo activity against most clinical isolates of Candida spp. and Aspergillus spp., as well as against other filamentous fungi.1,2 Convincing data are available for empirical antifungal therapy in patients with persistent fever and neutropenia and in non-neutropenic patients for the treatment of oesophageal candidiasis and invasive aspergillosis.3–6 Voriconazole is 60–100-fold more potent than fluconazole against Candida species and is active against non-albicans Candida species that are inherently resistant to fluconazole.7 The risk of fungal infections is significantly increased in intensive care patients because of their underlying life-threatening disease, long-term antibiotic use, mechanical ventilation, use of steroids or other kinds of immunosuppression, central venous catheter and renal replacement therapy.8
Continuous venovenous haemodiafiltration (CVVHDF) is a well-established extracorporal renal replacement therapy with a high clearance rate. Elimination of any given drug by renal replacement therapy is determined by several major factors that are membrane-specific (pore-size, filter surface area, adsorption, electrostatic charge and filter material), due to physico-chemical properties of the drug (molecular weight, protein-binding, water-solubility and molecular charge) or characteristics of the renal replacement technique used.9,10
Pharmacokinetic studies of antifungals in critically ill patients treated with CVVHDF are scarce. Taking into account the pharmacological properties of voriconazole, such as extensive hepatic metabolism and protein binding of 58%, no dosage adaptation seems to be necessary in critically ill patients undergoing CVVHDF.11 However, as tubular reabsorption is not present in anuric patients undergoing CVVHDF, the drug clearance might probably be higher than in physiological renal function, as reported in the case of fluconazole.12
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Patients and methods |
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Patients
Forty-seven intensive care patients with acute renal failure had renal replacement therapy during the study period. Nine intensive care patients with acute renal failure and suspected or proven fungal infection were included in the study. One of the nine patients had liver cirrhosis Child–Pugh C. Median duration of antifungal therapy was 10 days. All patients were anuric and had no additional diuresis. Age (mean ± SD) was 62 ± 13 years; height and weight (mean ± SD) were 169 ± 7 cm and 77 ± 12 kg, respectively. Acute physiologic and chronic health evaluation III (APACHE III) score (mean ± SD) was 93 ± 36. Patients' characteristics are illustrated in Table 1. All patients required mechanical ventilation. Concomitant drug therapy consisted mainly of intravenous catecholamines (n = 8), anticoagulation with heparin (n = 9), fentanyl (n = 5) and propofol (n = 4). All drugs were administered as clinically indicated by the attending physician. None of the patients received rifampicin, rifabutin, phenytoin, carbamazepine or long-acting barbiturates, which are known to reduce the serum concentration of voriconazole.11 None of the patients received sirolimus, tacrolimus, efavirenz, ergot alkaloids, quinidine or pimozide or calcium channel antagonists, which are known to increase in concentration by voriconazole.11 One patient who had kidney transplantation some years earlier (patient 5) received ciclosporin. None of the patients received midazolam, which is reported to increase the concentration of voriconazole.13 None of the patients had a known hypersensitivity or other intolerance to voriconazole or other triazole antifungal agents. The study protocol was approved by the local Ethics Committee (EK 405/2004).
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Continuous venovenous haemodiafiltration
CVVHDF was performed using an AN 69 HF hollow fibre haemofilter/dialyser (Prisma M100 Pre Set, Hospal Industrie, Meyzieu, France), as described previously.14 Briefly, the standard blood flow rate was 9 L/h. Pre-dilution fluid was infused at a rate of 1 L/h and dialysate flow was 1 L/h. Net fluid balance was adjusted according to clinical requirements. Filters and lines were steam sterilized. No filter change occurred during the study period.
Drug administration and sampling
All patients received voriconazole 6 mg/kg, the usual starting dose also prescribed to patients without renal failure, injected over a period of 60 min into a central venous catheter, different from the venous catheter used for CVVHDF. Four patients received voriconazole repeatedly during CVVHDF. These patients received 6 mg of voriconazole per kilogram body weight twice daily in the first 24 h and thereafter 4 mg per kilogram body weight twice daily. Blood samples were drawn from the pre-filter and post-filter line of the extracorporal circuit before and immediately after the end of the infusion as well as 60, 120, 180, 300 and 660 min after the end of the infusion; further blood samples were drawn immediately prior to the start and immediately after the end of consecutive voriconazole infusions. Ultradiafiltration samples, collected from the outlet of the ultradiafiltrate compartment of the haemodiafilter, were taken at corresponding times. All samples were centrifuged immediately and stored at –70° C until analysis.
The concentration of voriconazole in serum and ultradiafiltrate was determined by HPLC, with minor modification as described previously.15 Briefly, after the addition of 10 µL of a 100 mg/L internal standard (UK-115,794, Pfizer Limited, Sandwich, UK) to 500 µL of serum or ultradiafiltrate, the samples were buffered with 700 µL of 0.2 M borate buffer (pH 9.0). Samples were then extracted by solid-phase extraction (HLB, 30 mg, 1 mL Water Oasis columns; Waters, Milford, MA, USA). The columns were conditioned with separate washings in the following order: 1 mL of MeOH, 1 mL of H2O and 1 mL of 0.2 M borate buffer (pH 9.0). The buffered serum and ultrafiltrate samples were added to each respective column and washed with 1 mL of 0.2 M borate buffer and MeOH/H2O (50:50, v/v), respectively. Voriconazole and the internal standard were eluted with 1 mL of MeOH/glacial acetic acid (99:1, v/v), and 100 µL of the sample was injected onto the HPLC column. The chromatographic assay included a Merck ‘La Chrom’ system (Merck, Darmstadt, Germany), equipped with an L-7250 injector, an L-7100 pump, an L-7300 column oven (set at 35°C to keep the retention times constant), a D-7000 interface and an L-7400 UV-detector at 254 nm. Separation of voriconazole was carried out using a Hypersil BDS-C18 column (5 µm, 250 x 4.6 mm ID, Astmoor, UK) preceded by a Hypersil BDS-C18 pre-column (5 µm, 10 x 4.6 mm ID) at a flow rate of 1 mL/min. The mobile phase A consisted of potassium phosphate (50 mM, pH 3.0 with phosphoric acid) and heptanesulphonic acid (5 mM) and the mobile phase B consisted of methanol. The mobile phase was filtered through a 0.45 µm filter (HVLP04700, Millipore, Vienna, Austria). The gradient ranged from 30% methanol (0 min) to 70% B at 10 min, kept constant at 70% until 13 min and finally decreased linearly to 30% again at 15 min. The columns were allowed to re-equilibrate for 15 min between runs. Quantification was based on internal standard calibration by spiking drug-free human serum and ultradiafiltrate with standard solutions of voriconazole (Pfizer Limited; final concentrations ranging from 0.05, 0.1, 0.2, 0.5, 1, 2, 4, 6, 8, 10, 25 mg/L) using the ratio of the peak areas of voriconazole and the internal standard UK-115,794 (final concentration: 10 mg/L). For this method, the lower limit of quantification for voriconazole was determined to be 0.05 mg/L for serum and ultradiafiltrate. Intra-day values ranged from 3.2 to 8.7% and inter-day values from 3.8 to 9.5% using voriconazole concentrations of 0.1, 0.5, 1 and 10 mg/L serum.
The serum concentration time curves of voriconazole in plasma were adjusted to the data sets via non-linear iterative least-square regression analysis. Curve modelling was performed using the two-compartment open pharmacokinetic model with the program WinNonlin (version 1.5, Scientific Consulting, USA). The following parameters were calculated: area under the concentration curve from 0 to 12 h (AUC0–12) using the linear trapezoidal rule, total clearance (CLtot), volume of distribution (V), distribution half-life (t1/2
) and elimination half-life (t1/2ß). The sieving coefficient (S) was calculated as S = CUDF/CA, where CUDF is the concentration of voriconazole in the ultradiafiltrate and CA is the concentration of voriconazole in the pre-filter line of the extracorporal circuit. The clearance of haemodiafiltration (CLCVVHDF) was determined according to the formula CLCVVHDF=(QUF+QD)·(CUDF/CA)=(QUF+QD)·S, where QUF is the ultrafiltration rate and QD is the dialysation rate.
Total removal (Retot) in per cent of the drug was calculated as Retot=(Cmax–Cmin)/Cmax·100, where Cmax is the peak pre-filter serum concentration and Cmin is the pre-filter serum concentration after 12 h, respectively. Removal of voriconazole via haemodiafiltration (ReCVVHDF) in per cent was calculated as ReCVVHDF=CLCVVHDF/CLtot·100.
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Results |
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Voriconazole was well tolerated by all patients. Mean peak serum concentration of all nine patients after the first dose was 5.6 ± 2.9 mg/L at the pre-filter port and 4.6 ± 1.7 mg/L at the post-filter port. Mean trough levels were 1.1 ± 0.3 mg/L at the pre-filter port and 0.9 ± 0.3 mg/L at the post-filter port.
The pharmacokinetics of voriconazole during CVVHDF in eight patients without liver cirrhosis is summarized in Table 2; serum concentration versus time profile is illustrated in Figure 1.
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The peak and trough serum concentrations in the patient with liver cirrhosis were 3.5 and 1.3 mg/L. AUC0–12, CLtot, CLCVVHDF, sieving coefficient, V, t1/2
and t1/2ß were 19.8 mg·h/L, 4 L/h, 0.6 L/h, 0.31, 301 L, 1.0 h and 52 h in this patient; serum concentration versus time profile of this patient is illustrated in Figure 2.
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Follow-up examination of voriconazole plasma levels of consecutive doses was possible in four patients without cirrhosis during CVVHDF (Table 3).
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Discussion |
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Voriconazole has a predominantly extrarenal elimination.16 No dosage adaptation is necessary in patients with renal impairment.16 Although being constantly used in the treatment of serious fungal infections, data on voriconazole in patients undergoing renal replacement therapy are scarce. The aim of this study was to investigate the pharmacokinetics of voriconazole in critically ill patients with acute renal failure undergoing CVVHDF.
Peak and trough voriconazole serum concentrations in our study were consistent with a previous report in healthy volunteers who received the intravenous formulation.17 The sieving coefficient in our patients is in rational association with the reported protein binding of voriconazole of 58%.11 The volume of distribution is in the range reported for intravenous voriconazole.16 Elimination half-life of voriconazole in eight patients without hepatic impairment was slightly prolonged in comparison with healthy volunteers and was comparable with a previous report of a patient undergoing CVVHDF.17–19 Voriconazole's total clearance is in the range of previous reports in the eight patients without liver cirrhosis.17–19 In contrast, one patient who suffered from liver cirrhosis Child–Pugh C had clearly prolonged elimination half-life (52 h) and reduced total clearance (4 L/h). Voriconazole clearance via CVVHDF is low. No clear drug accumulation could be detected in patients who had CVVHDF during consecutive doses of voriconazole. Although we observed a slight increase in voriconazole's nadir plasma levels in some patients during follow-up (Table 3), the values were still in the reported range found in critically ill patients during steady state.20 In conclusion, the pharmacokinetics of voriconazole was not significantly altered in critically ill patients without cirrhosis requiring CVVHDF. In contrast, we found a markedly lower total clearance and extensively prolonged half-life in a critically ill patient with liver cirrhosis, indicating the necessity of a reduced maintenance dosing regimen following the usual loading regimen of voriconazole in patients with liver cirrhosis during CVVHDF. However, further data are required to confirm this first report of pharmacokinetics of voriconazole in a patient with liver cirrhosis Child–Pugh C.
Clearance of voriconazole via extracorporal renal replacement therapy depends on the renal replacement modality used. Table 4 summarizes the available pharmacokinetic data of voriconazole in patients undergoing renal replacement therapy. However, as the renal and extracorporal clearance solely count for 1% to 15% of the total clearance,16,18,21 overall pharmacokinetics of voriconazole is barely affected by any kind of renal replacement modality. Therefore, no dosage adjustment of voriconazole is required in patients during extracorporal renal replacement therapy.
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From the pharmacokinetic point of view, intravenous administration of voriconazole makes sense in patients with disturbed or unclear gastrointestinal absorption. It is well known that many patients requiring intensive care treatment and especially patients with renal or multiple organ failure frequently suffer from malabsorption and gastrointestinal dysfunction.22–26 Peak plasma concentrations of voriconazole close to steady state are achieved via an intravenous loading dose followed by a maintenance dose within the first 24 h of administration, but only 5–7 days following multiple oral administrations.11 Therefore, the intravenous route seems to be the more preferable route of initial administration of voriconazole in critically ill patients suffering from life-threatening fungal infections to achieve therapeutic voriconazole levels as early as possible. However, to minimize supposed interactions with the intravenous vehicle sulphobutylether ß-cyclodextrin, switching to the oral route seems rational as soon as sufficient gastrointestinal absorption is ensured.16,27,28 von Mach et al.27 observed accumulation of sulphobutylether ß-cyclodextrin in three patients during haemodialysis. In contrast, Mohr et al.29 reported that renal replacement therapy was capable of eliminating hydroxypropyl-ß-cyclodextrin, the intravenous vehicle of itraconazole, as effectively as in patients with normal renal function. However, extrapolation of these data to other cyclodextrins should be handled with caution as physicochemical and pharmacokinetic properties of different cyclodextrins may vary during renal replacement therapy. Further data are necessary to clarify the influence of renal replacement therapy on the pharmacokinetics of sulphobutylether ß-cyclodextrin.
We acknowledge potential limitations in our study. The number of patients in our study was small. However, this is a usual number of patients in pharmacokinetics studies of antimicrobial agents during continuous renal replacement therapies and currently the largest series on voriconazole pharmacokinetics during continuous renal replacement therapy.12,14,30–33 We cannot exclude a change in extracorporal voriconazole removal with different ultrafiltration or dialysate flow rates or using the post-dilution mode. However, according to pharmacokinetic reports during different extracorporal renal replacement modalities (Table 4) and according to the pharmacological properties of voriconazole, necessity of dosage adaptation of voriconazole is unlikely in critically ill patients during CVVHDF as long as no severe hepatic impairment is present. None of our patients received midazolam or barbiturates, which are reported to influence the elimination of voriconazole.11,13 Therefore, our data could not assess the influence of these drugs on voriconazole's pharmacokinetics in critically ill patients requiring CVVHDF. Intensive care practitioners should choose concomitant drugs with care in critically ill patients treated with voriconazole to avoid unwarranted drug interactions.
In conclusion, pharmacokinetics of voriconazole is barely affected by CVVHDF in critically ill patients without cirrhosis. We recommend standard dosing of voriconazole in critically ill patients without cirrhosis with anuric renal failure undergoing CVVHDF. In our patient with liver cirrhosis, a reduction in the maintenance dosing regimen following the usual loading regimen of voriconazole seems to be meaningful.
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Funding |
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Funding for this work was provided by Förderstipendium of the Medical University of Vienna.
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Transparency declarations |
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F. T. received research grants from Bayer, Hoechst, AstraZeneca, Sandoz, GlaxoSmithKline and Pfizer and served at the speakers bureaux of Astra Zeneca, Altana, Aventis, Bayer, MSD and Sandoz. All others: none to declare.
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Acknowledgements |
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We thank the nursing staff of the intensive care unit 13H1 at the Department of Internal Medicine III of the Medical University of Vienna, Austria, for their cooperation in this study.
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References |
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