1 Division of Clinical Pharmacology and Toxicology; 2 Division of Intensive Care Medicine; 4 Infectious Diseases Service, Department of Medicine, University Hospital, 1011 Lausanne, Switzerland; 3 Pharmacy DepartmentCREPIT 93, Avicenne Hospital, Bobigny, France
Received 4 March 2004; returned 22 March 2004; revised 15 April 2000; accepted 4 May 2004
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Abstract |
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Methods: Voriconazole pharmacokinetics were studied in a critically ill patient under CVVHDF. The analysis was carried out for 12 h following a 6 mg/kg dose. Voriconazole concentrations were measured by HPLC in blood inlet and outlet lines and in dialysate.
Results: The total body clearance of voriconazole was 20.3 L/h, with a terminal half-life of 13.7 h and a distribution volume of 399 L. The estimated sieving coefficient was 0.53 and the filtration-dialysis clearance 1.2 L/h.
Conclusions: CVVHDF does not significantly affect voriconazole disposition and requires no dosage adjustment.
Keywords: antifungals , renal failure , dialysis , pharmacokinetics
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Introduction |
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Materials and methods |
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A 70-year-old, 60 kg female patient with chronic renal insufficiency (baseline serum creatinine 195 µmol/L) was admitted to the Intensive Care Unit for adult respiratory distress syndrome due to Pneumocystis carinii pneumonia. The patient's condition deteriorated; she developed pancreatitis, disseminated intravascular coagulation and acute renal failure requiring the initiation of CVVHDF treatment. The CVVHDF apparatus was a PRISMA CFM (Hospal, Lyon, France) provided with a 0.9 m2 polyacrylonitrile hollow fibre filter (AN69 HF, Multiflow 100, Hospal, Lyon, France) connected through a double lumen venous catheter. The treatment conditions were set to 120 mL/min blood flow, 500 mL/h pre-dilution flow, patient subtraction of 220 and 1000 mL/h counter-current dialysate solution flow. A deterioration of the respiratory status was observed and a reassessment revealed the presence of Aspergillus fumigatus in the cultures. Treatment with intravenous voriconazole (6 mg/kg twice at a 14 h interval as loading dose, followed by 4 mg/kg every 12 h) was begun. The patient died 8 days later from multiple organ failure.
Drug sampling and assay
The analysis was carried out on the second 6 mg/kg dosing after patient's informed consent had been obtained, with blood samples being collected from the arterial and venous lines and dialysate samples from the output line. The administered dose was assessed with precision by recording the infused volume (137 mL) and measuring the voriconazole concentration in a sample of the infused solution. The residual urine was collected over the 12 h dosing interval for voriconazole determination. Blood samples were centrifuged and plasma, dialysate, urine and infused solution samples stored at 20°C until analysis.
Voriconazole concentrations were measured by an HPLC method6 after solid phase extraction, using a reversed-phase Luna-5 µm C18 column (250 x 4.5 mm) at room temperature. The mobile phase consisted of 0.01 M N,N,N',N'-tetramethylethylenediamine phosphate buffer (adjusted to pH 7.4 with phosphoric acid) added to acetonitrile (55:45); detection was made by UV at 254 nm. The lower limit of quantification was 0.2 mg/L, and the inter- and intraday coefficients of variation were lower than 12% at all concentration levels.
Pharmacokinetic analysis
The concentrationtime curves resulting from the arterial, venous and dialysate lines are shown in Figure 1. Plasma voriconazole concentrationtime data were analysed using non-compartmental calculations, with the AUC being estimated by the log-trapezoidal method (without extrapolation beyond the dosing interval). The total body clearance was estimated as the dose divided by AUC, the apparent terminal elimination rate constant (z) by log-linear least square regression, with elimination half-life (t1/2) derived as log(2)/
z and terminal volume of distribution (Vz) as CLTOT/
z. The renal clearance was obtained as the ratio of voriconazole excreted unchanged in urine over AUC. A sieving coefficient was calculated as the ratio of concentration in dialysate over arterial blood. Then a filtration-dialysis clearance was estimated as the product of Sc multiplied by total filtrate and dialysate flow (detailed calculations according to Ref. 7).
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Results and discussion |
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Footnotes |
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References |
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2
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Pearson, M., Rogers, P. D., Cleary, J. D. et al. (2003). Voriconazole: a new triazole antifungal agent. Annals of Pharmacotherapy 37, 42032.
3
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Purkins, L., Wood, N., Ghahramani, P. et al. (2002). Pharmacokinetics and safety of voriconazole following intravenous- to oral-dose escalation regimens. Antimicrobial Agents and Chemotherapy 46, 254653.
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Herbrecht, R., Denning, D. W., Patterson, T. F. et al. (2002). Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. New England Journal of Medicine 347, 40815.
5
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Forni, L. G. & Hilton, J. P. (1997). Continuous hemofiltration in the treatment of acute renal failure. New England Journal of Medicine 336, 13039.
6
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Pennick, G. J., Clark, M., Sutton, D. A. et al. (2003). Development and validation of a high-performance liquid chromatography assay for voriconazole. Antimicrobial Agents and Chemotherapy 47, 234850.
7
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Robatel, C., Decosterd, L. A., Biollaz, J. et al. (2003). Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. Journal of Clinical Pharmacology 43, 132940.
8 . Purkins, L., Wood, N., Greenhalgh, K. et al. (2003). The pharmacokinetics and safety of intravenous voriconazolea novel wide-spectrum antifungal agent. Journal of Clinical Pharmacology 56, 29.[CrossRef]
9 . Pfizer Global Research & Development (2001). Briefing document for voriconazole, for the FDA Antiviral Drug Products Advisory Committee, pp. 1-56. [Online.] http://www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2_01_Pfizer.pdf (1 April 2004, date last accessed).