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

Abstract

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.

Effect of Therapeutic Drug Monitoring and Cytochrome P450 2C19 Genotyping on Clinical Outcomes of Voriconazole: A Systematic Review

“…The available studies demonstrated that there may be value in genotype-guided dosing: adult studies reported fewer subtherapeutic VTCs without greater toxicity, and the pediatric study showed that patients quickly reached therapeutic ranges while lowering toxicity and drug discontinuation rates compared with a historical control. 72,73,86 Thus, more studies are needed to better understand the potential clinical utility of CYP2C19-guided dosing. Indeed, the difficulty of undertaking clinical trials in this area leads to small sample sizes, which poses further issues with generalizability and allelic representation.…”

“…RMs on recommended dosing showed higher VTCs than RMs on standard dosing (2.7 vs 0.6 µg/mL; P = 0.001), and subtherapeutic concentrations were avoided in RMs on recommended dosing (83.3% vs 46.2%; P = 0.02). 72 No significant differences in drug-related discontinuations or toxicities were found. 72 Treatment success was not reported; however, hospital-acquired nodular pneumonia rate was marginally lower in the CYP2C19-guided cohort compared with historical control (2.1 vs 2.2 cases per 1000 neutropenic days; P = 0.46).…”

“…72 No significant differences in drug-related discontinuations or toxicities were found. 72 Treatment success was not reported; however, hospital-acquired nodular pneumonia rate was marginally lower in the CYP2C19-guided cohort compared with historical control (2.1 vs 2.2 cases per 1000 neutropenic days; P = 0.46). 72 In the prospective study by Patel et al, 73 89 hematopoietic stem cell transplant (HSCT) patients were genotyped before receiving prophylactic oral voriconazole.…”

“…Two studies examined the effect of prospective CYP2C19guided voriconazole dose selection (Table 4). 72,73 In the prospective study by Hicks et al, 72 263 acute myeloid leukemia patients were CYP2C19-genotyped before receiving prophylactic oral voriconazole. 72 RMs were recommended 300 mg twice daily, URMs were recommended to avoid voriconazole, and all others received a standard twice-daily 200-mg dose.…”

“…72,73 In the prospective study by Hicks et al, 72 263 acute myeloid leukemia patients were CYP2C19-genotyped before receiving prophylactic oral voriconazole. 72 RMs were recommended 300 mg twice daily, URMs were recommended to avoid voriconazole, and all others received a standard twice-daily 200-mg dose. RMs on recommended dosing showed higher VTCs than RMs on standard dosing (2.7 vs 0.6 µg/mL; P = 0.001), and subtherapeutic concentrations were avoided in RMs on recommended dosing (83.3% vs 46.2%; P = 0.02).…”