Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

Han, Kelong; Capitano, Blair; Bies, Robert R.; Potoski, Brian A.; Husain, Shahid; Gilbert, Sébastien; Paterson, David L.; McCurry, Kenneth R.; Venkataramanan, Raman

doi:10.1128/aac.00504-10

Cited by 83 publications

(83 citation statements)

References 35 publications

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“…A good correlation between voriconazole AUC 0 -12 and trough concentration at steady state was identified in adults and children in earlier studies (21,22). The correlation between estimated voriconazole AUC 0 -12 and C min in this study is expressed as follows (also, see Fig.…”

Section: Figmentioning

confidence: 63%

Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Liu

Mould

2014

Antimicrob Agents Chemother

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bTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC 0 -12 ] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479). Invasive aspergillosis (IA) is an important cause of morbidity and mortality in patients with hematological malignancies, as well as those who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. Antifungal combination therapy with voriconazole (an azole; both intravenous [IV] and oral formulations are available) and anidulafungin (an echinocandin; IV only) is an intriguing possibility for the treatment of IA, due to their different mechanisms of action and lack of pharmacokinetic (PK) drug-drug interaction (1-3). Voriconazole inhibits fungal cytochrome P450 (CYP)-dependent 14-␣-sterol demethylase, an essential enzyme in the synthesis of ergosterol (a component of the fungal cell membrane). Anidulafungin is a 1,3-␤-D-glucan synthase inhibitor which interferes with fungal cell wall synthesis. A number of in vitro studies and animal models have demonstrated additive or synergistic activities of voriconazole and echinocandins against Aspergillus species (4-7), indicating that two mechanisms of action may provide an additional benefit over one mechanism alon...

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Section: Figmentioning

confidence: 63%

Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Liu

Mould

2014

Antimicrob Agents Chemother

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“…The samples were vortexed and centrifuged at 14,000 rpm for 15 min. Hundred microliters of filtered clear supernatant was injected into the chromatographic system [18,19].…”

Section: Sample Collection and Processingmentioning

confidence: 99%

Plasma Voriconazole Estimation by HPLC

2015

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Voriconazole, an antifungal drug exhibiting wide inter-individual variability, is an ideal candidate for therapeutic drug monitoring (TDM). The aim of the present study was to standardize a simple, sensitive and rapid high performance liquid chromatography (HPLC) method with ultraviolet detection to determine plasma voriconazole concentration. The HPLC method consisted of a combination of acetonitrile and water (7:3) as mobile phase with 1 ml/min flow rate and detection at 255 nm. Plasma protein precipitation was carried out using perchloric acid and the filtered supernatant was passed through C18 column (250 9 4.6 mm, 5 lm) for the separation of voriconazole. The limit of quantification of voriconazole was 0.2 mg/L. The assay was validated with a linearity of 0.2-15 mg/L and used clinically for TDM in patient samples. The interassay precision was below 15 % for routine quality control samples. Weight based voriconazole doses were prescribed to 26 patients for empirical treatment of invasive fungal infections. Voriconazole therapy was managed from the baseline drug levels and follow up analysis reflected achievement in clinical efficacy. Routine TDM of voriconazole may reduce adverse events and improve the treatment response in invasive fungal infections.

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“…There is significant interpatient variability in drug exposure, reflecting nonlinear saturable pharmacokinetics, drugdrug interactions, CYP2C19 genetic polymorphisms, and physiological conditions associated with underlying diseases (2,28,35). Voriconazole serum troughs are good measures of drug exposure (14,15). Low troughs are associated with therapeutic failure among patients with IFIs, and dose adjustments for undetectable concentrations are reported to improve treatment efficacy (10,13,21,24,28,32,36,37,39).…”

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confidence: 99%

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

Mitsani

Nguyen

Shields

et al. 2012

Antimicrob Agents Chemother

117

125

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ABSTRACTVoriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n= 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n= 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P= 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P= 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (P= 0.01) and among patients with no trough of >1.5 μg/ml (P= 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P= 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.

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Bioavailability and Population Pharmacokinetics of Voriconazole in Lung Transplant Recipients

Cited by 83 publications

References 35 publications

Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Plasma Voriconazole Estimation by HPLC

Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

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