Altered Pharmacokinetics of Voriconazole in a Patient with Liver Cirrhosis

Weiler, Stefan; Zoller, Heinz; Graziadei, I.; Vogel, Wolfgang; Bellmann‐Weiler, Rosa; Joannidis, Michael; Bellmann, Romuald

doi:10.1128/aac.00791-07

Cited by 42 publications

(30 citation statements)

References 11 publications

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“…Similar to studies with other drugs, population pharmacokinetic investigations have shown that interpatient variability is more common in certain patient cohorts (12,27,55,59,60,65,82,90,91,92,102). For example, in a recent study of bone marrow transplant recipients receiving voriconazole for antifungal prophylaxis, 87 patients had voriconazole trough concentrations assayed after 5 days of therapy.…”

Section: -Fcmentioning

confidence: 99%

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

Andes

Pascual

Marchetti

2009

Antimicrob Agents Chemother

433

342

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Section: -Fcmentioning

confidence: 99%

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

Andes

Pascual

Marchetti

2009

Antimicrob Agents Chemother

433

342

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“…Large inter-and intraindividual variabilities in voriconazole plasma concentrations regardless of the route of administration or the type of patient population have been documented and discussed in the literature (2,17,19,22,23,33,38,40,42,45). Factors associated with interindividual variability of voriconazole exposure include liver dysfunction, alcohol abuse in the past (47), concomitant use of potent CYP450 inducers or inhibitors (10,12), CYP2C19 genetic polymorphisms (including poor as well as ultrarapid metabolizers) (13,20,46), gastrointestinal abnormalities (e.g., mucositis or diarrhea) (38) impairing drug absorption, and intake with or without food (15).…”

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confidence: 99%

Voriconazole Pharmacokinetics in Liver Transplant Recipients

Johnson

Han

Capitano

et al. 2010

Antimicrob Agents Chemother

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The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (V ss /F), and half-life (t 1/2 ) were 5.8 ؎ 5.5 liters/h, 94.5 ؎ 54.9 liters, and 15.7 ؎ 7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC 0-ؕ ) and trough voriconazole plasma concentrations.

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“…Voriconazole presented an almost 10-fold prolongation of halflife in two patients with severe liver cirrhosis (12,22). For caspofungin, a dose reduction is recommended when it is administered to patients with liver cirrhosis although its elimination appears to be only minimally affected by hepatic impairment (19).…”

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confidence: 99%

Pharmacokinetics of Amphotericin B Colloidal Dispersion in Critically Ill Patients with Cholestatic Liver Disease

Weiler

Überlacher²,

Schöfmann³

et al. 2012

Antimicrob Agents Chemother

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The pharmacokinetics of lipid-bound and liberated amphotericin B (AMB) was assessed in 11 critically ill patients with cholestatic liver disease (CSLD) and in 9 subjects with normal liver function treated with AMB colloidal dispersion (ABCD). Exposure to lipid-bound AMB was higher in patients with CSLD. Levels of liberated AMB were elevated by CSLD only after the first dose, whereas its pharmacokinetics was unaffected at steady state. The standard dosage of ABCD is probably adequate for patients with CSLD. Liver disease has been identified as a risk factor for invasive fungal infections (IFIs) such as invasive aspergillosis in critically ill patients (15,16). Amphotericin B (AMB) has a broad antimycotic spectrum and is therefore a cornerstone in the treatment of IFIs. Because of its renal toxicity, however, conventional AMB is frequently replaced by less toxic lipid formulations such as AMB colloidal dispersion (ABCD; Amphocil, Amphotec). ABCD contains AMB as a cholesteryl sulfate complex forming disc-like structures of 74 to 170 nm in diameter (5). AMB does not undergo hepatic metabolism, but it is eliminated in part via the bile. ABCD is rapidly taken up by liver macrophages (11,25). Clinical studies on the influence of hepatic impairment on AMB pharmacokinetics are lacking so far. Therefore, the pharmacokinetics of lipidbound (colloidal) AMB and of AMB liberated from its lipid binding was assessed under single-dose and steady-state conditions in critically ill patients with and without cholestatic liver disease (CSLD) treated with ABCD.The study was approved by the local ethics committee. Time-AMB concentration profiles were determined in critically ill patients with CSLD (defined as plasma bilirubin of Ͼ10 mg/dl due to CSLD) and in a control group comprising critically ill patients with approximately normal hepatic function (bilirubin of Ͻ1.28 mg/dl). Patients with a plasma bilirubin level between 1.28 and 10 mg/dl and patients with a plasma bilirubin level of Ͼ10 mg/dl caused by disorders other than CSLD (e.g., hemolysis) were excluded from the study. ABCD was administered for suspected or proven IFIs over 4 h at a dose of ϳ4 mg/kg of body weight. In order to avoid infusion-related toxicity, ϳ2 mg/kg was given on day 1. In all patients enrolled, conventional AMB deoxycholate was contraindicated because of its renal toxicity. Blood samples of 2 ml were taken from an arterial line on day 1 of ABCD therapy (single dose) and on day 5 or later (steady state) before ABCD administration as well as 4,6,8,12, and 24 h after the start of infusion. Lipid-bound (colloidal) AMB and AMB that had been liberated from its lipid binding in the plasma were separated by solid-phase extraction and quantified by high-performance liquid chromatography as described previously (10). The pharmacokinetics of lipid-bound, liberated, and total AMB was calculated by Kinetica 2000 (InnaPhase Corporation, Champs-sur-Marne, France) using a noncompartmental model. The area under the concentration-time curve from time zero to 24 h (AUC 0 -24...

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Altered Pharmacokinetics of Voriconazole in a Patient with Liver Cirrhosis

Cited by 42 publications

References 11 publications

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

Antifungal Therapeutic Drug Monitoring: Established and Emerging Indications

Voriconazole Pharmacokinetics in Liver Transplant Recipients

Pharmacokinetics of Amphotericin B Colloidal Dispersion in Critically Ill Patients with Cholestatic Liver Disease

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