Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients

Trifilio, Steve; Pennick, Gennethel; Pi, J.; Zook, Jennifer; Golf, M.; Kaniecki, K.; Singhal, Seema; Williams, Stephanie; Winter, Jane N.; Tallman, Martin S.; Li, Gordon; Frankfurt, Olga; Evens, Andrew M.; Mehta, Jayesh

doi:10.1002/cncr.22568

Cited by 189 publications

(128 citation statements)

References 16 publications

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“…Furthermore, polymorphisms in the CYP2C19 isoform are associated with slow VRC metabolism and may lead to two-to four folds higher VRC exposure [9]. Corroborating the potential of drug-drug interactions, it's known that in patients with haematologic malignancy, the correlation between VRC concentration and daily dose is poor [10].…”

Section: Patientsmentioning

confidence: 99%

A New HPLC Validated Method for Therapeutic Monitoring Of Triazoles in Human Plasma: First Results in Leukaemic Patients

Francia

Cardalana²,

P³

et al. 2015

Clin Exp Pharmacol

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Therapeutic drug monitoring of triazoles is widely used in clinical practice to optimize therapy, especially in those patients who need antifungal treatment as co-medications. Here it is described development and validation of a new chromatographic method in order to quantify voriconazole and posaconazole in human plasma by ultraviolet detection.After liquid extraction of analytes from plasma using acetonitrile, samples are evaporated to dryness and then reconstituted in mobile phase for chromatographic separation. Analysis is achieved on C18 reverse phase column and eluate is monitored at 250 nm. Mobile phase consisted of 35% water, 15% methanol, 50% acetonitrile. Flavone was used as internal standard; retention times (minutes) were, respectively, for voriconazole 3.9, posaconazole 7.9, flavone 7.1.Accuracy and variability were assayed by inter-and intra-day validation, conducted on three separate days. Methodology was used for the analysis of plasma samples of acute myeloid leukaemia patients in therapy with voriconazole or posaconazole for treatment of fungal infections, in order to perform therapeutic monitoring of antifungal drugs levels.Mean inter-and intra-day accuracy and variability were acceptable for both compounds; thus, method developed resulted linear in the range 0.125-8 µg/mL. Limits of quantification and limits of detection for voriconazole and posaconazole are, respectively, 0.100 and 0.050 µg/mL, and 0.030 and 0.020 µg/mL.It has been observed that voriconazole and posaconazole circulating levels achieved in patients are on average below the therapeutic range defined in literature.In conclusion, method developed and validated in order to quantify voriconazole and posaconazole in human plasma is accurate and precise; it is easily applicable and reproducible, and, therefore, it could be an useful tool in clinical routine to better manage patients in case of multi-therapy approach.

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Section: Patientsmentioning

confidence: 99%

A New HPLC Validated Method for Therapeutic Monitoring Of Triazoles in Human Plasma: First Results in Leukaemic Patients

Francia

Cardalana²,

P³

et al. 2015

Clin Exp Pharmacol

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“…Studies in adults have shown that under-dosing voriconazole in patients with invasive fungal disease results in significant morbidity and mortality while high serum levels result in more frequent side effects [93,94,[106][107][108]. In children the data are more limited.…”

Section: Clinical Studies In Adultsmentioning

confidence: 99%

“…Observational studies have noted therapeutic failure with voriconazole plasma levels <1 µg/ ml and increase in side effects when levels exceed 5-6µg/ml [93,107,108,118,119]. Transient hepatotoxicity and visual disturbances are most commonly reported.…”

Section: Therapeutic Drug Monitoring (Tdm) Of Voriconazolementioning

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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“…In patients with haematologic malignancy, the correlation between voriconazole concentration and daily dose is poor, in keeping with intrapatient variability. 150 In pooled data from ten published clinical trials, the median average plasma concentration was reported as 2.51 mg/mL. 139 In a study assessing voriconazole as directed therapy for IFI (n = 28), voriconazole levels were measured in 17 patients with disease progression.…”

Section: Voriconazolementioning

confidence: 99%

Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders

Worth

Blyth

Booth

et al. 2008

Internal Medicine Journal

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Antifungal prophylaxis, empirical therapy and treatment of established fungal infections in the haematology population may be associated with significant toxicity or drug interactions leading to sub-therapeutic antifungal drug concentrations and poorer clinical outcomes. These risks may be minimised by clinical assessment, laboratory monitoring of biochemical or haematological indices, avoidance of particular drug combinations and dose modification in certain circumstances. Specific measures, such as the optimal timing of oral drug administration in relation to meals, use of pre-hydration and electrolyte supplementation may also be required. For certain agents, therapeutic drug monitoring (TDM) is warranted where non-compliance, non-linear pharmacokinetics, a narrow therapeutic window, suspected drug interaction or unexpected toxicity are encountered. Pharmacokinetics and pharmacodynamics of clinical relevance to the haematology population are discussed for the azole, polyene and echinocandin classes of antifungal agents. The evidence supporting an association between TDM and enhanced treatment outcomes is presented for individual antifungal drugs, and recommendations for clinical practice are provided. Further randomised study of newer antifungal agents, such as posaconazole, is required to explore the potential for improved clinical outcomes in association with TDM.Understanding a drug's pharmacokinetics and its pharmacodynamic effects affords the clinician the capacity to optimize drug exposure while minimizing or avoiding drug interactions and toxicities. Therapeutic drug monitoring (TDM) may also be employed during the treatment period to ensure that the selected drug dosage falls within the therapeutic window for an individual patient.These clinical caveats are particularly relevant to the haematology population where the frequent requirement for polypharmacy and the complexity of comorbidities can significantly influence the success of antifungal therapy. This section of the guidelines describes the potential drugdrug interactions and toxicities related to antifungal use and how they may be avoided. It also considers the latest

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Monitoring plasma voriconazole levels may be necessary to avoid subtherapeutic levels in hematopoietic stem cell transplant recipients

Cited by 189 publications

References 16 publications

A New HPLC Validated Method for Therapeutic Monitoring Of Triazoles in Human Plasma: First Results in Leukaemic Patients

A New HPLC Validated Method for Therapeutic Monitoring Of Triazoles in Human Plasma: First Results in Leukaemic Patients

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

Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders

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