Evidence Of Therapeutic Drug Monitoring (TDM) In The Treatment Of Invasive Aspergillosis (IA) With Voriconazole (VCZ) In Cancer Patients

Invasive aspergillosis is a life-threatening complication in hematological cancer patients (pts). VCZ is the established first-line standard treatment of IA. Failure of VCZ therapy in IA due to lack of efficacy or adverse events (AEs) occurs in 30-40% of treated pts. VCZ has a nonlinear pharmacokinetic profile and exhibits considerable variability of drug exposure. Therefore, TDM of VCZ may help to improve treatment results in pts with IA. While TDM is recommended by some authors, evidence-based data on the clinical use of TDM in pts treated with VCZ for IA are scarce. Our present analysis assessed published studies for evidence-based criteria guiding TDM of VCZ to improve efficacy and safety of IA therapy in cancer pts. Evidence-based guidance is needed to support decisions on the use of TDM in clinical routine VCZ therapy of IA.

Literature searches of Medline, Cochrane database and conference abstracts were performed. We identified 25 clinical studies (comprising a total of 3822 pts, range 5 - 1091) reporting on the use of TDM for VCZ. For each study, strength of recommendation and quality of evidence was categorized according to criteria defined by Kish et al. (Clin Infect Dis 2001). Each trial was was assessed separately.for the categories efficacy, toxicity, timing of TDM and dose adjustment. The majority of trials included cancer pts. Two trials reported on a pediatric population (>0 - < 12 yrs of age), 21 trials reported on adults only, while the remaining 5 trials reported on children and adults. Evaluable TDM data were reported for 3313 pts, whereas 509 pts were not included for TDM for various reasons. VCZ plasma levels were determined by HPLC in 23 trials. A total of 8266 VCZ serum levels were reported. Of the 7 prospective studies, 1 randomized prospective, double-blind trial included pts treated with VCZ or fluconazole. The primary endpoint of a significant AE reduction by TDM of VCZ versus no TDM was not reached (CI), while efficacy was higher in pts managed with TDM (BI). The other studies were observational or retrospective cohort studies. 18 reports provided data on both intravenous and oral use of VCZ, 4 trials reported on intravenous VCZ and 3 on oral VCZ only. 13/25 trials were evaluable for evidence on TDM regarding efficacy, 10/25 for toxicity. High inter- and intra-study variability was observed for timepoints of VCZ measurement (day 1 to >day 210) and number of VCZ plasma levels (n = 2 to >40). Across the studies, VCZ levels >5-5.5 mg/L were found to be associated with toxicity (BII), while reaching minimum levels of >1-2 mg/L appeared to improve efficacy (BII). Timing (CIII), frequency (CIII) and intervention thresholds (CIII) of VCZ TDM remain an open question.

Although a substantial number of studies is published on TDM in VCZ therapy of IA, there is still no robust evidence for recommendations in clinical practice. VCZ levels >5-5.5 mg/L were reported to be associated with toxicity (BII), while minimum levels of >1-2 mg/L may improve efficacy (BII). However, timing (CIII) and frequency (CIII) of TDM als well as intervention thresholds (CIII) and dosage increments for adjustment of VCZ plasma levels need to be established in a multicenter randomized clinical trial to provide a scientifically adequate basis for guidance on TDM of VCZ for IA in cancer pts.

Karthaus:Pfizer: Honoraria; MSD: Honoraria; Gilead: Honoraria; Astellas: Honoraria. Lehrnbecher:Gilead: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Astellas: Honoraria. Buchheidt:Gilead: Honoraria; MSD: Honoraria; Astellas: Honoraria; Pfizer: Honoraria.