Voriconazole Associated Adverse Drug Events and Drug Monitoring in Lung Transplant (LTx) Recipients

Abstract

Voriconazole is the drug of choice for prophylaxis and treatment of Aspergillus infection in LTx recipients. Voriconazole has a narrow therapeutic index; thus, therapeutic drug monitoring (TDM) is required to prevent treatment failure and reduce the risk of adverse drug events (ADE). We aim to determine the frequency and type of ADE associated with voriconazole and describe voriconazole dosing and TDM in LTx recipients. This retrospective cohort study included adult LTx recipients who received at least one dose of voriconazole between January 2016 to May 2019. The frequency and severity of ADE, discontinuation of voriconazole due to ADE were captured. Therapeutic voriconazole levels were defined as trough levels between 1-5.5 mg/L. 75 voriconazole exposures in 64 LTx recipients occurred during the study period. Liver enzyme elevation was the most common ADE. 87% (66/75) had liver enzyme elevation, 39% (29/75) and 43% (32/75) had ≥ Grade 1 elevation in GGT and ALP, and AST/ALT, respectively (defined by CTCAE v5.0). 45% (34/75) had ≥1 neurological toxicity. 28% (21/75) of cases had ADE that resulted in early discontinuation or change in therapy. The median starting dose for all indications was 3.54 mg/kg twice daily. 85% (64/75) of cases had documented voriconazole levels. The average time to first level was 7.5 days, 36% (23/64) had subtherapeutic levels, 58% (37/64) had therapeutic levels, and 6% (4/64) had supratherapeutic levels. 38% (24/64) had ≥ Grade 1 liver enzyme elevation with subtherapeutic or therapeutic levels, 3% (2/64) with supratherapeutic levels. Of the subtherapeutic levels, 35% (8/23) were using voriconazole for treatment of Aspergillus with a median starting dose of 3.73 mg/kg twice daily. In cases where therapeutic concentrations were attained at the first level, the average time to therapeutic level was 6.9 days; in contrast, when therapeutic concentrations were not attained at the first level, the average time to the first therapeutic level was 28.8 days. LTx recipients frequently experience ADE due to voriconazole. Despite adequate initial weight-based dosing, 36% still achieved subtherapeutic levels. The time to first therapeutic voriconazole level was significantly longer if therapeutic levels were not achieved at the first level. TDM monitoring alone does not predict voriconazole toxicities in our LTx cohort.