Annotation of Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline information
for voriconazole and CYP2C19

last updated 03/15/2017

Summary

The CPIC dosing guideline for voriconazole recommends selecting an alternative agent that is not dependent on CYP2C19 metabolism in adults who are CYP2C19 ultrarapid metabolizers, rapid metabolizers or poor metabolizers. In pediatric patients, an alternative agent should be used in patients who are ultrarapid metabolizers or poor metabolizers. In pediatric rapid metabolizers, therapy should be initiated at recommended standard case dosing, then therapeutic dosing monitoring should be used to titrate dose to therapeutic trough concentrations.

Annotation

December 2016

Table 1: Dosing recommendations for voriconazole treatment based on CYP2C19 phenotype for adult patients

Adapted from Tables 1 and 2 of the 2016 guideline manuscript.

Likely PhenotypeGenotypesbExamples of diplotypesImplications for pharmacologic measuresTherapeutic recommendationsClassification of Recommendationse
Ultrarapid metabolizer (~2-5% of patients)aAn individual carrying two increased function alleles*17/*17In patients for whom an ultrarapid metabolizer genotype is identified, the probability of attainment of therapeutic voriconazole concentrations is small with standard dosing.Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.fModerateg
Rapid metabolizer (~2-30% of patients)aAn individual carrying one normal function allele and one increased function allele*1/*17In patients for whom a rapid metabolizer genotype is identified, the probability of attainment of therapeutic concentrations is modest with standard dosing.Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.fModerate
Normal metabolizerc (~35-50% of patients)aAn individual carrying two normal function alleles*1/*1Normal voriconazole metabolismInitiate therapy with recommended standard of care dosing.fStrong
Intermediate metabolizer (~18-45% of patients)aAn individual carrying one normal function allele and one no function allele or one no function allele and one increased function allele*1/*2, *1/*3, *2/*17dHigher dose-adjusted trough concentrations of voriconazole compared to normal metabolizers.Initiate therapy with recommended standard of care dosing.fModerate
Poor metabolizer (~2-15% of patients)aAn individual carrying two no function alleles*2/*2, *2/*3, *3/*3Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events.Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.f In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.Moderate

a See the CYP2C19 Frequency Table for race specific allele and phenotype frequencies.

b Assignment of allele function can be found on PharmGKB (CYP2C19 Allele Definition Table) and citations for allele function can be on PharmGKB (CYP2C19 Allele Functionality Table).

c Based on the CPIC term standardization project, the term "Normal Metabolizer" will be used instead of the term "Extensive Metabolizer" in all new and updated CPIC guidelines.

d The predicted metabolizer phenotype for the *2/*17 genotype is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the no function CYP2C19*2 (Sibbing et al., 2010). See the 2016 Supplement for a more comprehensive list of predicted metabolizer phenotypes.

e Rating scheme is described in the 2016 Supplement

f Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, TDM, and comorbidities.

g Recommendations based upon data extrapolated from patients with CYP2C19*1/*17 genotype


Table 2: Dosing recommendations for voriconazole treatment based on CYP2C19 phenotype for pediatric patients

Adapted from Tables 1 and 3 of the 2016 guideline manuscript.

Likely PhenotypeGenotypesbExamples of diplotypesImplications for pharmacologic measuresTherapeutic recommendationsClassification of Recommendationse
Ultrarapid metabolizer (~2-5% of patients)aAn individual carrying two increased function alleles*17/*17In patients for whom an ultrarapid metabolizer genotype is identified, the probability of attainment of therapeutic voriconazole concentrations is small.Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.f,gModerate
Rapid metabolizer (~2-30% of patients)aAn individual carrying one normal function allele and one increased function allele*1/*17In patients for whom a rapid metabolizer genotype is identified, the probability of attainment of therapeutic concentrations is variable.Initiate therapy with recommended standard case dosing.f Use therapeutic dose monitoring to titrate dose to therapeutic trough concentrations.g,hModerate
Normal metabolizerc (~35-50% of patients)aAn individual carrying two normal function alleles*1/*1Normal voriconazole metabolismInitiate therapy with recommended standard of care dosing.fStrong
Intermediate metabolizer (~18-45% of patients)aAn individual carrying one normal function allele and one no function allele or one no function allele and one increased function allele*1/*2, *1/*3, *2/*17dHigher dose-adjusted trough concentrations of voriconazole compared to normal metabolizers.Initiate therapy with recommended standard of care dosing.fModerate
Poor metabolizer (~2-15% of patients)aAn individual carrying two no function alleles*2/*2, *2/*3, *3/*3Higher dose-adjusted trough concentrations of voriconazole and may increase probability of adverse events.Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazolef,i. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.Moderatei

a See the CYP2C19 frequency table for race specific allele and phenotype frequencies.

b Assignment of allele function can be found on PharmGKB (CYP2C19 Allele Definition Table) and citations for allele function can be on PharmGKB (CYP2C19 Allele Functionality Table).

c Based on the CPIC term standardization project, the term "Normal Metabolizer" will be used instead of the term "Extensive Metabolizer" in all new and updated CPIC guidelines.

d The predicted metabolizer phenotype for the *2/*17 genotype is a provisional classification. The currently available evidence indicates that the CYP2C19*17 increased function allele is unable to completely compensate for the no function CYP2C19*2 (Sibbing et al., 2010). See the 2016 Supplement for a more comprehensive list of predicted metabolizer phenotypes.

e Rating scheme is described in the 2016 Supplement

f Further dose adjustments or selection of alternative therapy may be necessary due to other clinical factors, such as drug interactions, hepatic function, renal function, species, site of infection, TDM, and comorbidities.

g Achieving voriconazole therapeutic concentrations in the pediatric population with ultrarapid and rapid metabolizer phenotypes in a timely manner is difficult. As critical time may be lost in achieving therapeutic concentrations, an alternative antifungal agent is recommended in order that the child receives effective antifungal therapy as soon as possible.

h Meticulous therapeutic drug monitoring is critical for rapid metabolizers. There is insufficient evidence to distinguish a CYP2C19*1/*17 and *1/*1 pediatric patient due to large variability in trough concentrations.

i Recommendation based upon data extrapolated from adults.

CPIC voriconazole guideline

Total publications: 1

Reference
1. Clinical Pharmacogenetics Implementation Consortium (CPIC®) Guideline for CYP2C19 and Voriconazole Therapy. Clinical pharmacology and therapeutics. 2016. Moriyama Brad, Obeng Aniwaa Owusu, Barbarino Julia, Penzak Scott R, Henning Stacey A, Scott Stuart A, Agúndez José A G, Wingard John R, McLeod Howard L, Klein Teri E, Cross Shane, Caudle Kelly E, Walsh Thomas J. PubMed

Guideline History