Prospective CYP2C19-Guided Voriconazole Prophylaxis in Patients With Neutropenic Acute Myeloid Leukemia Reduces the Incidence of Subtherapeutic Antifungal Plasma Concentrations

• Published in: Clinical pharmacology and therapeutics Vol. 107; no. 3; p. 563
• Main Authors: Hicks, J Kevin, Quilitz, Rod E, Komrokji, Rami S, Kubal, Timothy E, Lancet, Jeffrey E, Pasikhova, Yanina, Qin, Dahui, So, Wonhee, Caceres, Gisela, Kelly, Kerry, Salchert, Yasmina S, Shahbazian, Kevin, Abbas-Aghababazadeh, Farnoosh, Fridley, Brooke L, Velez, Ana P, McLeod, Howard L, Greene, John N
• Format: Journal Article
• Language: English
• Published: United States 01.03.2020
• Subjects: Adult; Aged; Aged, 80 and over; Alleles; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; Cytochrome P-450 CYP2C19 - genetics; Dose-Response Relationship, Drug; Female; Genotype; Humans; Incidence; Leukemia, Myeloid, Acute - complications; Male; Middle Aged; Mycoses - prevention & control; Neutropenia - etiology; Prospective Studies; Risk Management; Voriconazole - administration & dosage; Voriconazole - pharmacokinetics; Young Adult
• ISSN: 1532-6535
• DOI: 10.1002/cpt.1641

A risk mitigation strategy was implemented to determine if a higher prophylactic voriconazole dosage in patients with CYP2C19 rapid metabolizer neutropenic acute myeloid leukemia (AML) reduces the incidence of subtherapeutic trough concentrations. Patients with AML (n = 263) were preemptively genotyped for CYP2C19*2, *3, and *17 alleles as part of a single-center prospective, interventional, quality improvement study. CYP2C19 rapid metabolizers (CYP2C19*1/*17) were recommended to receive interventional voriconazole 300 mg twice daily, ultrarapid metabolizers (CYP2C19*17/*17) were recommended to avoid voriconazole, and all others received the standard prophylactic dosage of 200 mg twice daily. In this real-world setting, 202 patients (76.8%) were prescribed prophylactic voriconazole, and of these patients 176 (87.1%) received CYP2C19-guided prophylactic dosing. Voriconazole trough concentrations were obtained for 41 of the 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole. Interventional voriconazole resulted in higher plasma trough concentrations (median 2.7 μg/mL) compared with the standard prophylactic dosage (median 0.6 μg/mL; P = 0.001). Subtherapeutic concentrations were avoided in 83.8% of CYP2C19 rapid metabolizers receiving interventional dosage compared to 46.2% receiving standard dosage (P = 0.02). CYP2C19 genotyping to preemptively guide prophylactic voriconazole dosing is feasible and may be a potential strategy for reducing the risk of subtherapeutic trough concentrations that potentiate breakthrough fungal infections.