Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study

Myrianthefs, Pavlos; Markantonis, Sophia L.; Evaggelopoulou, Penelope; Despotelis, Stratos; Evodia, E; Panidis, Dimitrios; Baltopoulos, George

doi:10.1016/j.ijantimicag.2009.12.021

Cited by 34 publications

(27 citation statements)

References 23 publications

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“…Myrianthefs et al and Ueda et al also reported that standard doses of voriconazole resulted in highly variable concentrations on trough (less than 0.1 to 11.4 µg/mL and 0.22-12.77 µg/mL). 5,21) In addition, they reported there was no correlation between the voriconazole concentration on trough and its dose. The large variability of voriconazole concentration on trough was not thought to be due to dosage in clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Saturated Metabolism of Voriconazole <i>N</i>-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses

Yamada

Mino

Yagi

et al. 2015

Biological & Pharmaceutical Bulletin

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Key words voriconazole; metabolite; nonlinear pharmacokinetics; N-oxidation; CYP2C19Voriconazole is a second-generation triazole antifungal agent. Compared with other azole antifungal agents, it has potent activity against a broader spectrum of clinically significant fungal pathogens, including Aspergillus, Candida, and some unusual organisms. 1) In clinical settings, voriconazole is initially administered for the treatment of invasive pulmonary aspergillosis and empirical antifungal therapy in patients with persistent fever and neutropenia and in non-neutropenic patients. 2,3) Therapeutic drug monitoring is recommended for voriconazole in order to ensure its safety and efficacy. An association between successful therapeutic outcome in fungal infections and plasma voriconazole concentrations has been reported. 4) The lowest effective concentration on trough of voriconazole was reported as 1-2 µg/mL. [4][5][6][7][8] In contrast, a higher plasma concentration on trough of voriconazole was associated with the incidence of adverse effects, such as ocular, neurological, or hepatic toxicity. These adverse effects were observed in patients whose plasma concentration on trough of voriconazole exceeded 4 µg/mL. 4,7,9,10) However, there is large interindividual variability in the plasma concentration on trough of voriconazole. The prediction of voriconazole concentration on trough remains extremely difficult in clinical settings.Voriconazole is available as intravenous and tablet formulations in Japan. The standard maintenance doses of voriconazole are 3 or 4 mg/kg for injection and 150, 200 or 300 mg twice daily for oral administration. Voriconazole exhibits a nonlinear pharmacokinetic profile at the clinical dose. 11) Voriconazole is metabolized mainly in the liver to the major metabolite voriconazole N-oxide (N-oxide). N-Oxide accounts for 72% of all circulating metabolites in the plasma. 12) Although vorizonazole N-oxide has minimal antifungal activity compared with voriconazole, it has been found to inhibit the metabolic activity of CYP3A4 and CYP2C19 in vitro. 12) Because voriconazole is mainly metabolized via CYP2C19 or CYP3A4, the N-oxide may have an effect on the metabolic profile of voriconazole. The determination of N-oxide together with voriconazole can be useful in evaluating the metabolic process of voriconazole.Several studies investigated factors related to the nonlinear pharmacokinetics of voriconazole. 11,13) The saturation of metabolic clearance is believed to cause nonlinear pharmacokinetics because voriconazole is eliminated predominantly by metabolism. However, there are no clinical reports on the relationship of voriconazole and its major N-oxide metabolite that take into consideration CYP2C19 gene variants. As previously described, CYP molecular species participate in the metabolism of voriconazole and CYP2C19 plays the most dominant role. The genetic variants of CYP2C19 exhibited a large interindividual variation in voriconazole exposure. [14][15][16] The genetic variants of CYP2C19 may affect the...

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Section: Discussionmentioning

confidence: 99%

Saturated Metabolism of Voriconazole <i>N</i>-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses

Yamada

Mino

Yagi

et al. 2015

Biological & Pharmaceutical Bulletin

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“…7,8) Moreover, when special treatments were carried out, the pharmacokinetic profile of VRC might display significant variations in critically ill patients, like extracorporeal membrane oxygenation and continuous venous hemofiltration. 4,[9][10][11] Moreover, the different CYP2C19 polymorphism, 12,13) body weight, 14) and life style 15) of Chinese population may result in a varied pharmacokinetic profile of VRC compared to that of westerner's.…”

Section: )mentioning

confidence: 99%

“…4,[9][10][11] Moreover, the different CYP2C19 polymorphism, 12,13) body weight, 14) and life style 15) of Chinese population may result in a varied pharmacokinetic profile of VRC compared to that of westerner's. In addition, patients in the intensive care units (ICU) are more susceptive to fungal infections, 8) and suffered more complicated antifungal treatment due to their extreme body conditions and large concomitant drugs. Thus it's necessary to describe the VRC exposure in Chinese ICU patients in order to better understand its dosage-effect and -toxicity relationship.…”

Section: )mentioning

confidence: 99%

Population Pharmacokinetics in China: The Dynamics of Intravenous Voriconazole in Critically Ill Patients with Pulmonary Disease

Chen

Xie

Liang

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Studies in both healthy volunteers [85][86][87] and critically ill adults [88,89] have demonstrated non-linear PK that is thought to be due to saturable first-pass metabolism and decreased systemic clearance. Consequently small changes in dose may affect large changes in serum drug levels.…”

Section: Pharmacologymentioning

confidence: 99%

Triazole Use in the Nursery: Fluconazole, Voriconazole, Posaconazole, and Ravuconazole

Watt¹,

Manzoni²,

Cohen‐Wolkowiez³

et al. 2013

Current Drug Metabolism

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Invasive fungal infections in infants admitted to the neonatal intensive care unit are common and often fatal. The mainstay of therapy against invasive fungal infections is antifungal agents. Over the last two decades, the development and approval of these drugs evolved tremendously, and the azole class emerged as important agents in the treatment and prevention of invasive fungal infections. Among the azoles, fluconazole has been used extensively due to its favorable pharmacokinetics, excellent activity against Candida spp, and safety profile. This drug has been well studied in children but data for its use in infants are largely limited to Candida prophylaxis studies. Voriconazole, a second generation triazole, has excellent activity against Candida and Aspergillus spp. However, data on its use in neonates are extremely limited. Posaconazole and Ravuconazole are the newest agents of the triazole family. The antimicrobial spectrum of posaconazole is similar to voriconazole, but with additional activity against zygomycetes. Experience with posaconazole in children is very limited, and there are no reports of its use in infants. Ravuconazole is not approved for use by the FDA but studies in animals and humans show that it is often fungicidal and has favorable pharmacokinetics. In conclusion, the management of invasive fungal infections has progressed greatly over the last two decades with the azole antifungals playing a significant role. Related to this class, future research is needed in order to better assess dosing, safety, schedules and areas of use of these agents in infants admitted to the neonatal intensive care unit.

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Monitoring plasma voriconazole levels following intravenous administration in critically ill patients: an observational study

Cited by 34 publications

References 23 publications

Saturated Metabolism of Voriconazole <i>N</i>-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses

Saturated Metabolism of Voriconazole <i>N</i>-Oxidation Resulting in Nonlinearity of Pharmacokinetics of Voriconazole at Clinical Doses

Population Pharmacokinetics in China: The Dynamics of Intravenous Voriconazole in Critically Ill Patients with Pulmonary Disease

Triazole Use in the Nursery: Fluconazole, Voriconazole, Posaconazole, and Ravuconazole

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