2107. Azole Therapeutic Drug Monitoring (TDM) in a Multiracial Cohort with Varied Pharmacogenetics

Abstract

BackgroundVoriconazole (VOR) and posaconazole (POS) exhibit wide pharmacokinetic variability. Various factors including race and genetic polymorphisms are at play and this may affect treatment response. We aim to evaluate the utility of VOR/POS TDM among Southeast Asians that are predominantly intermediate/poor VOR metabolizers.MethodsAll adults with VOR/POS TDM performed at our institution from 2015 to 2018 were included. We determined proportion of patients and doses required to achieve TDM targets [(2 – 5.5 mg/L (VOR) or ≥ 0.7 and ≥ 1.0 mg/L (POS prophylaxis and treatment respectively)], and correlate levels with treatment efficacy and safety.ResultsVOR/POS TDM was performed mostly among patients with hematological malignancy or solid-organ transplant (146/174, 83.9%). Less than half (32/70, 45.7%) of patients on VOR achieved target—18 (25.7%) were < 2 mg/L while 20 (28.5%) had levels > 5.5 mg/L. Doses required to achieve TDM target ranged from 1.9–11.4 mg/kg/day. Drug interactions, critically ill state and change in drug formulation were major causes of intra-patient variability. One-fifth (n = 14) experienced transaminitis; corresponding VOR trough levels were 0.5–> 7.5 mg/L. Neurotoxicity was also seen in 3 (4.3%) patients—all 3 had VOR trough ≥ 6.7 mg/L and saw symptom resolution upon dose reduction. There appears to be no association between the achievement of TDM targets and response rates. Majority (81/104, 77.9%) of patients on POS achieved TDM targets. Patients prescribed POS tablet were significantly more likely to attain targets compared with suspension 600 mg/day [19/26 (73.0%) vs. 27/62 (43.5%), P < 0.05] and 800 mg/day [17/26 (65.3%) vs. 4/16 (25.0%), P < 0.05)]. Of 23 with sub-therapeutic levels, 19 (82.6%) responded to dose increase and/or change in acid-reducing agents. Breakthrough infection occurred despite troughs ≥ 0.7 mg/L [5/42 (11.9%) vs. 2/40 (5.0%) when < 0.7 mg/L (P = 0.3)]. Treatment failure was observed in 2 patients (troughs > 1.0 mg/L).ConclusionVOR/POS TDM should be implemented in Southeast Asians due to significant unpredictability in dose exposure and potential to avoid need for switch to alternative anti-fungals due to intolerability. Higher POS trough cutoff may be required for effective anti-fungal prophylaxis.Disclosures All authors: No reported disclosures.