Phenotype-guided dosing of prophylactic voriconazole may reduce fungal infections, costs
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Phenotype-guided dosing strategies can increase the proportion of patients with hematologic malignancies who achieve a therapeutic drug concentration of prophylactic voriconazole, according to results of two studies published in Clinical Pharmacology & Therapeutics.
A CYP2C19 genotype-guided dosing strategy for the administration of prophylactic voriconazole increased the number of patients with therapeutic drug concentrations needed to prevent invasive fungal infections, both studies showed.
“Previous data suggest that genetically rapid metabolizers have low drug concentrations for voriconazole. ... In many different practices and settings, we check drug concentrations because we know they are associated with response, primarily in cases where patients have low drug concentrations and are at risk for drug failure,” Jai N. Patel, PharmD, BCOP, CPP, chair of cancer pharmacology and pharmacogenomics at Levine Cancer Institute at Atrium Health and a HemOnc Today Editorial Board Member, told Healio.
One study — led by James K. Hicks, PharmD, PhD, of Moffitt Cancer Center — examined genotype-guided voriconazole prophylaxis for patients with acute myeloid leukemia. Patel served as lead author of the other study, which assessed patients who received prophylactic voriconazole after allogeneic hematopoietic stem cell transplant for a variety of hematologic malignancies.
Patients in both studies were neutropenic after undergoing induction therapy with standard chemotherapy, leaving them with suppressed white blood cell counts and at risk for fungal infections. The standard of care for these patients is prophylactic voriconazole to prevent infection.
There already is a known drug exposure-clinical response relationship among these patients, Patel said, and previous data indicated a significant correlation between CYP2C19 genotype and drug exposure.
“If there's a significant relationship between genetics and drug exposure, then why not do genetic testing, alter the dose and see if that improves exposure?” Patel said. “If we improve drug exposure, then we should be able to improve clinical response.”
Prophylaxis in AML
Hicks and colleagues conducted a single-center prospective study of 263 patients (median age, 64 years; range, 19-86; 53% male) with AML who were genotyped for CYP2C19*2, *3 and *17 alleles to guide dosing of prophylactic voriconazole.
Rapid metabolizers (CYP2C19*1/*17) received voriconazole dosed at 300 mg twice daily. Ultrarapid metabolizers (CYP2C19*17/*17) received isavuconazonium (Cresemba, Astellas Pharma) instead of voriconazole. Other study participants received the standard 200 mg twice-daily prophylactic dose of voriconazole.
Approximately three-quarters (76.8%; n = 202) of patients received prophylactic voriconazole; of these, 176 received CYP2C19-guided prophylactic dosing.
Researchers obtained voriconazole trough concentrations for 41 of 58 (70.7%) CYP2C19 rapid metabolizers prescribed prophylactic voriconazole.
Interventional voriconazole resulted in higher median plasma trough concentrations than the standard prophylactic dosage (2.7 g/mL vs. 0.6 g/mL; P = .001).
Subtherapeutic concentrations were avoided for 83.8% of CYP2C19 rapid metabolizers who received the interventional dosage compared with 46.2% who received the standard voriconazole dose (P = .02).
Four of 46 rapid metabolizers (8.7%) who received the 300 mg twice-daily voriconazole dose experienced neurotoxicity, and three (6.5%) experienced elevated liver transaminases that required discontinuation of voriconazole.
Hicks and colleagues noted their study was limited by its underrepresentation of racial and ethnic minorities. Also, the small sample size made the study inadequately powered to determine if CYP2C19 genotyping was cost-effective in its ability to reduce the number of breakthrough fungal infections in this patient population.
“Implementation of CYP2C19 genotyping in a neutropenic population with AML to preemptively guide prophylactic voriconazole dosage is feasible,” Hicks and colleagues wrote. “CYP2C19 genotyping to optimize voriconazole dosing may be a potential strategy for reducing the risk [for] subtherapeutic trough concentrations that potentiate breakthrough fungal infections.”
Prophylaxis after HSCT
Patel and colleagues conducted a prospective observational study to evaluate the impact of CYP2C19 genotype-guided prophylactic voriconazole dosing for adults with hematologic malignancies who underwent HSCT.
The study included 89 patients (mean age, 54 years; 61.8% male) with a primary diagnosis of AML (37.1%), myelodysplastic syndrome (21.4%), lymphoma (19.1%), acute lymphoblastic leukemia (13.5%) or chronic myeloid leukemia (4.5%).
Poor, intermediate and normal CYP2C19 metabolizers received voriconazole 200 mg twice daily, whereas rapid and ultrarapid CYP2C19 metabolizers received voriconazole 300 mg twice daily.
Among all patients, 29% had subtherapeutic concentrations compared with 50% in a historical control group (P < .001). Subtherapeutic concentration rates in the study cohort were 0% for poor metabolizers, 26% for intermediate metabolizers, 50% for normal metabolizers and 16% for rapid/ultrarapid metabolizers.
Researchers reported a voriconazole success rate of 78% compared with 54% for the historical control group (P < .001), with no patients developing an invasive fungal infection.
Genotype-guided dosing resulted in an estimated per-patient savings of $4,700 compared with simulated controls in a separate cost analysis.
“We didn't have any fungal infections in our study, and the cost associated with that significantly outweighs the cost of implementing genetic testing,” Patel told Healio. “This is speculative because it wasn’t validated prospectively in a randomized clinical trial, but we still wanted to provide at least some estimate of whether we could save some costs.”
Clinical implications
Both studies provide evidence that phenotype-guided dosing can increase the proportion of patients who achieve a therapeutic drug concentration and — at least in these patient populations — this can happen with no change in treatment-related toxicities, Patel said.
Although genetic testing upfront may cost more, the savings associated with reducing the number of new fungal infections among immunosuppressed patients could outweigh the cost of the testing.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) curates pharmacogenomics data to provide evidence-based guidelines for how to translate genetic test results into actionable prescribing decisions. The group maintains guidelines for both voriconazole and CYP2C19 genotyping, with much of that data based on retrospective studies, Patel said.
“Their guidelines actually recommend that — for genetically rapid or ultrarapid metabolizers — providers should consider using an alternative antifungal, but there were no prospective data to validate that recommendation,” Patel told Healio. “In our study, we’re showing that we don’t necessarily need to consider an alternative antifungal. If voriconazole is still the drug of choice, we may just need to consider higher doses for those patients.”
The clinical impact of these studies will be greatest for institutions that either are already testing for CYP2C19 or are considering testing, Patel said.
“We now have evidence-based data to show that we can adjust the dose safely and improve drug exposure for these patients,” he said. “As we look 5 years down the road, we’re going to see more institutions doing more large-scale pharmacogenomics testing for many different types of genes, with CYP2C19 being one of the most popular ones.”
Patel said he hopes the data from these studies will lead to a new iteration of CPIC guidelines.
“Adjusting the dose can improve drug exposure without compromising safety and improve clinical response,” he said. “I think these studies will result in greater uptake of dose adjustments based on genotype.” – by Drew Amorosi
For more information:
Jai N. Patel, PharmD, BCOP, CPP, can be reached at Levine Cancer Institute at Atrium Health, Department of Cancer Pharmacology, 1021 Morehead Medical Drive, Suite 3100, Charlotte, NC 28204; email: jai.patel@atriumhealth.org.
Disclosures: The studies were supported in part by grants from American Society of Health System Pharmacists, Collins Family Trust, DeBartolo Family Personalized Medicine Institute and Pinellas Partners. Hicks reports consultant roles with Quest Diagnostics and 23andMe, and research funding from OneOme. Patel reports no relevant financial disclosures. Please see the studies for all other authors’ relevant financial disclosures.
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