Utility of Voriconazole Monitoring and Factors Affecting Its Levels in Patients Undergoing Hematopoietic Stem Cell Transplantation. Single Center Experience From India.

Voriconazole (vori) is used for prophylaxis against fungal infections in BMT. Under and over-dosing of vori may influence the efficacy and safety of therapy, respectively. There is large variability in vori exposure following standard dose administration. Utility of Therapeutic Drug Monitoring (TDM) of vori in patients with invasive mycoses has been demonstrated and recommended that trough concentrations should be maintained between 1–5.5 μg/mL. Based on these observations we started TDM of vori in BMT patients at our centre to target trough plasma concentration of 1–6 μg/mL. Few reports are available on the TDM of vori in BMT. We report our experience.

All patients (autologous-65, allogeneic-64) who received vori prophylaxis during peritransplant period between September 2008 and January 2012 were included. Vori prophylaxis was started atleast 3 days prior to start of conditioning regimen in all patients before April 2011. Since April 2011, patients undergoing autologous transplant received vori 1 day after completion of chemotherapy. All patients above 12 years received oral loading dose of 6 mg/kg (upto maximum of 400 mg) 12 hourly on first day followed by 4mg/kg as maintenance. Intravenous dosing was used if patients had severe mucositis or developed febrile neutropenia. Patients less than 12 years received 7mg/kg 12 hourly continuously. Vori levels were measured on 5^th-7^th day after start of loading dose. Subsequent levels were done 2– 4 weekly till discontinuation of drug. If first level was < 1 or > 6 μg/ml, each dose was increased or decreased by 50% respectively and levels repeated after a week. Vori was continued for at least 100 days for all patients undergoing allogeneic transplant and longer if patients were on steroids due to graft vs host disease. Autologous transplant patients received it for 28 days. Incidence of breakthrough fungal infection was recorded as definite (blood culture positivity or histological evidence), probable (CT scan evidence with positive fungal PCR or galactomannan positivity) or possible (CT evidence only). Demographic and laboratory factors affecting the levels evaluated were age, sex, height, weight, body surface area (BSA), liver and renal function parameters. Concomitant drugs being used were recorded for any effect on vori levels. Vori levels in plasma were determined by a validated HPLC assay. Paired samples were compared using t-test or Wilcoxin sign rank test. Influence of covariates on vori levels were analyzed by linear regression with backward elimination. Interaction between concomitant drugs and their effects on vori levels was determined by ANCOVA after adjusting for baseline values.

One hundred twenty-nine patients were monitored during this period. The median age was 24.6 years. The median number of TDM was 3 (1–32) per patient. High inter and intra-patient variability was observed (coefficient of variation = 73% and 45% respectively). Twenty-eight patients (21.7%) had trough levels < 1 μg/mL after the first monitoring. Twenty-one patients had their dose modified after first monitoring (16 due to very low levels and 5 due to high levels). Thirteen (80%) patients achieved target trough concentration after dose escalation. Dose reduction resulted in sub-optimal levels in 3 of 5 patients. Twenty – four patients who had adequate levels at first TDM had fall in level below 1 μg/mL subsequently during the 2^nd or 3^rd TDM. This coincided with the introduction of steroids for treatment. Introduction of steroids significantly reduced vori trough levels (presteroid mean- 2.67 μg/ml, post steroid mean- 1.47μg/ml; P=0.014).Similarly use of cyclosporine (CSA) also significantly decreased vori levels (pre CSA mean-2.65μg/ml, post CSA mean-1.91μg/ml; P=0.023). The effect of steroids and CSA on vori levels were independent of each other. None of the demographic or laboratory parameters influenced vori levels. Breakthrough fungal infections were seen in 5 patients (definite-1, probable-3, possible-1).

Voriconazole level monitoring should be done in all patients who are on steroids and CSA post transplant. No demographic or laboratory parameter affected voriconazole levels in our study. Incidence of breakthrough fungal infection is low in patients who are monitored with drug levels.

No relevant conflicts of interest to declare.