Monitoring trough voriconazole plasma concentrations in haematological patients: real life multicentre experience

Abstract

The objective of this retrospective study was to evaluate results from voriconazole therapeutic drug monitoring (TDM) in haematological patients in routine clinical practice. Between 2005 and 2010, 1228 blood samples were obtained from 264 haematological patients (median 3 samples/patient; range 1-27) receiving voriconazole for targeted/preemptive treatment of invasive aspergillosis (IA) (46.3% of samples), empirical therapy (12.9%) or prophylaxis (40.8%). A high-pressure liquid chromatography assay was used to analyse voriconazole concentrations. Clinical and laboratory data were analysed retrospectively. The median of the detected voriconazole plasma concentration was 1.00 μg ml(-1) (range <0.20-13.47 μg ml(-1)). Significant inter- and intra-patients variability of measured concentrations (81.9% and 50.5%) were identified. With the exception of omeprazole administration, there was no relevant relationship between measured voriconazole concentrations and drug dose, route administration, age, gender, CYP2C19*2 genotype, gastrointestinal tract abnormality, administration via nasogastric tube, serum creatinine, and liver enzymes. However, per patient analysis identified significant role of individual voriconazole dose and drug form change on measured plasma concentration. Measured voriconazole concentrations did not correlate with the treatment outcome of patients with IA. We only identified a limited number of adverse events related to voriconazole therapy; however, the median plasma concentration was not different from concentrations measured in samples without reported toxicity. Our retrospective study has suggested that routine monitoring of voriconazole plasma concentrations has probably only a limited role in daily haematological practice.

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

“…However, the effect of PPIs, especially pantoprazole on the VRC C min , is far from fully under- stood since clinical studies investigating VRC pharmacokinetics have demonstrated either increased (3) or decreased (6, 41) VRC C min in patients treated with pantoprazole compared to those in untreated PPI patients. Since it is well known that PPIs competitively inhibit CYP2C19 (3,7,40), taken together, these results suggest that PPI treatment significantly contributes to the variability of VRC C min .…”

“…Thus, a therapeutic target of between 1 and 4 to 6 mg/liter for VRC C min has recently been proposed by the British Society for Medical Mycology (5). However, the VRC C min is frequently below this efficacy threshold in patients suffering from hematologic malignancies (6,7), notably in AHSCT patients (8).…”

Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch Regimens in Immunocompromised Japanese Pediatric Patients

“…The Japanese practice guidelines for therapeutic drug monitoring (TDM) of voriconazole also recommend a target trough level of 1 to 2 g/ml in terms of clinical efficacy, and in patients with a trough level of Ͼ4 to 5 g/ml, elevated liver function test results potentially attributable to voriconazole should be considered (32). On the other hand, 2 recently published retrospective analyses of large-scale voriconazole TDM data from real-world clinical settings showed no associations between the voriconazole concentrations and clinical outcomes or treatmentrelated toxicity (33,34). An analysis of data from a recent phase 3 study in adult patients with IA also did not establish positive associations between the voriconazole concentrations and clinical outcomes or treatment-related toxicity when voriconazole was administered as a monotherapy (21).…”

The incidence of invasive fungal infections in neutropenic patients with acute leukemia and myelodysplastic syndromes receiving primary antifungal prophylaxis with voriconazole

“…Recent literature has reported mixed results concerning the association of voriconazole therapeutic drug monitoring. Park et al demonstrated that therapeutic drug monitoring reduces drug discontinuation due to adverse events and improves treatment response [28]; while Racil et al failed to establish improved outcomes with measured voriconazole concentrations [29]. The true magnitude of the utility of a standardized protocol for monitoring serum concentrations of nonweight based dosing for voriconazole as primary antifungal prophylaxis has yet to occur in a prospective, randomized trial and remains controversial.…”

“…The true magnitude of the utility of a standardized protocol for monitoring serum concentrations of nonweight based dosing for voriconazole as primary antifungal prophylaxis has yet to occur in a prospective, randomized trial and remains controversial. Notwithstanding the controversy of the therapeutic value of a serum voriconazole trough concentration of >1.0 and >2.0 mg/ml in the setting of voriconazole prophylaxis, [29]. The particular vulnerability of leukemia patients undergoing chemotherapy favors therapeutic drug monitoring to ensure adequate drug absorption.…”