Voriconazole therapeutic drug monitoring in allogeneic hematopoietic stem cell transplant recipients

Abstract

Summary:Voriconazole, a new antifungal agent, is increasingly being used after HSCT. The hepatic cytochrome P450 isoenzyme 2C19 plays a significant role in voriconazole metabolism. As CYP2C19 exhibits significant genetic polymorphism, some patients metabolize voriconazole poorly resulting in increased plasma drug levels. The clinical significance of this is unknown, and the utility of monitoring voriconazole levels is unclear. Steady-state trough plasma voriconazole levels were obtained in 25 allogeneic HSCT recipients using an HPLC assay. Patients had drug levels checked once (n ¼ 13), twice (n ¼ 10), or X3 times (n ¼ 2) 5-18 days (median 10) after starting voriconazole or dose modification. The 41 voriconazole levels were 0.2-6.8 lg/ml (median 1.6); 6 (15%) were o0.5 (possibly below the in vitro MIC 90 for Aspergillus spp.). Voriconazole concentrations correlated with aspartate aminotranferase (AST) (r ¼ 0.5; P ¼ 0.0009) and alkaline phosphatase (r ¼ 0.34; P ¼ 0.03), but not with creatinine, bilirubin and alanine aminotransferase (ALT). Since liver dysfunction is common after HSCT, it was not possible to determine if elevated AST and alkaline phosphatase levels were the cause or the consequence of higher voriconazole levels. We conclude that trough voriconazole levels vary considerably between patients, and suggest monitoring levels in patients receiving voriconazole for confirmed fungal infections, and in those with elevated AST or alkaline phosphatase levels. Bone Marrow Transplantation (2005) 35, 509-513.

Breakthrough fungal infections after allogeneic hematopoietic stem cell transplantation in patients on prophylactic voriconazole

“…We have also implemented voriconazole therapeutic drug monitoring. 11 The purpose of this retrospective review was to determine the efficacy of voriconazole in preventing invasive fungal infections in our patient population and to find out if there was any correlation between drug levels and efficacy.…”

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

“…Therapeutic drug monitoring of serum trough voriconazole levels are obtained at physician and pharmacist discretion in an attempt to optimize serum concentrations according to previous studies [24][25][26][27]. In our study, attainment of an initial serum voriconazole trough concentration of >1.0 and >2.0 mg/ml was measured in 86 and 70% of patients, respectively.…”

“…Voriconazole-resistant or refractory Aspergillus spp. and Mucorales should be considered in neutropenic patients receiving voriconazole prophylaxis [25]. Recent literature has reported mixed results concerning the association of voriconazole therapeutic drug monitoring.…”

“…We can feel reasonably comfortable with absorption of oral voriconazole given the achievement of median serum voriconazole trough concentrations of 2.5 and 2.8 mg/ml in those that did and did not develop and IFI, respectively. Factors associated with a large variability in voriconazole exposure following standard dose administration were not assessed and sequential quantifications of serum voriconazole trough concentrations were only performed in very few subjects limiting the ability to assess for intrapatient variability found in other studies, most of which occurred in transplant patients [24][25][26]30,31]. Interpatient variability was evident given the large range in serum voriconazole concentrations and the poor correlation utilizing the standard dosing of voriconazole 200 mg twice daily on a mg/kg basis.…”

Antifungal stewardship considerations for adults and pediatrics

“…However, other studies have reported that voriconazole TDM improves the efficacy and safety for patients with invasive mycoses. [91][92][93] In a recent report, Park and colleagues randomized 110 adults with IFI into TDM or non-TDM groups. 92 Voriconazole dosage was adjusted to meet the target range of 1-5.5 mg/L based on the serum trough measured on the fourth day after initiation.…”