title: Prospective, observational study of voriconazole therapeutic drug monitoring among lung transplant recipients receiving prophylaxis: factors impacting levels of and associations between serum troughs, efficacy, and toxicity.
abstract: Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ≥ 60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥ 2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤ 1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤ 1.5 μg/ml (P = 0.01) and among patients with no trough of >1.5 μg/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml.
authors.affiliation: Divisions of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Mitsani
authors.forename: M Hong
authors.initials: MH
authors.lastname: Nguyen
authors.forename: Ryan K
authors.initials: RK
authors.lastname: Shields
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Toyoda
authors.forename: Eun J
authors.initials: EJ
authors.lastname: Kwak
authors.forename: Fernanda P
authors.initials: FP
authors.lastname: Silveira
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Pilewski
authors.forename: Maria M
authors.initials: MM
authors.lastname: Crespo
authors.forename: Christian
authors.initials: C
authors.lastname: Bermudez
authors.forename: Jay K
authors.initials: JK
authors.lastname: Bhama
authors.forename: Cornelius J
authors.initials: CJ
authors.lastname: Clancy
mesh_terms: D000328:Adult; D000368:Aged; D000935:Antifungal Agents / Q000097:blood / Q000493:pharmacokinetics; D002490:Central Nervous System / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D003550:Cystic Fibrosis / Q000097:blood / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D016903:Drug Monitoring; D005260:Female; D005658:Fungi / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000517:prevention & control*; D011446:Prospective Studies; D011658:Pulmonary Fibrosis / Q000097:blood / Q000188:drug therapy / Q000382:microbiology / Q000473:pathology; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics*; D014481:United States; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole