Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy

Amsden, Jarrett R.; Gubbins, Paul O.

doi:10.1080/17425255.2017.1391213

Cited by 47 publications

(31 citation statements)

References 113 publications

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“…The recommended dose is 200 mg (intravenously or orally) every 8 h for 48 h, followed by 200 mg once daily as a maintenance dose applied 12–24 h after the last loading dose. Isavuconazole is mainly metabolized by the hepatic cytochrome 450 (CYP) 3A4/5 [1, 2], with polymorphisms [ CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746)] that lead to unexpected kinetic profiles, as observed for other drugs such as tacrolimus [3] (an immunosuppressive drug). To date, the pharmacokinetic-pharmacodynamic relationship has not been established for patients [4], as the only information available was obtained using rabbits [5, 6] or a murine model [7, 8].…”

Section: Introductionmentioning

confidence: 99%

Isavuconazole Kinetic Exploration for Clinical Practice

et al. 2018

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BackgroundIsavuconazole is a new antifungal prodrug for the treatment of invasive aspergillosis and mucormycosis. As no clear pharmacokinetic-pharmacodynamic relationship has been established for patients, therapeutic drug monitoring is not currently required. However, as isavuconazole is a new drug, clinicians are sometimes sceptical about the exposure achieved in their patients and seek pharmacokinetic exploration. A minimal response consists of determining that the patient’s pharmacokinetic profile agrees with profiles reported by Desai et al. using concentrations from the SECURE study.MethodsBased on one concentration and Desai et al.’s population-pharmacokinetic model, it is possible to estimate a patient’s most likely pharmacokinetic profile. If a patient’s pharmacokinetic profile is close to the profiles reported by Desai et al., therapeutic drug monitoring is not required. In contrast, when the pharmacokinetic profile differs from the Desai et al. profiles, isavuconazole concentration monitoring and pharmacokinetic profile modeling are the only methods for obtaining information on a patient’s exposure and the efficacy of isavuconazole.ResultsFour patients presented with surprising pharmacokinetic profiles, unexplained by drug interactions or cytochrome P450 3A4/5 polymorphisms. For two of them, a drug dosage adjustment was proposed and applied by clinicians, together with a check for a new pharmacokinetic profile a few days later.ConclusionsCollecting one blood sample just before the first maintenance dose to make an early estimation of the patient’s most likely pharmacokinetic profile is one method of identifying patients with outlier pharmacokinetic behavior.

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Section: Introductionmentioning

confidence: 99%

Isavuconazole Kinetic Exploration for Clinical Practice

et al. 2018

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“…Our study confirmed these findings, as none of the patients exposed to either triazoles or echinocandins in included studies had fulminant hepatitis or acute liver failure, yet adverse events rate was significantly higher in the groups exposed to triazoles. Additionally, all triazoles interact with cytochrome P450, especially with CYP3A4 and CYP3A5, while voriconazole interacts also with CYP2C19 [25] , and their potential to inhibit elimination of other drugs metabolized through the same enzymes is much higher than that of echinocandins [26] .Echinocandins are not metabolized through cytochromes (except micafungin in minor extent) and therefore do not influence elimination of other drugs that are oxidized at these enzymes in liver [21] .…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of triazoles versus echinocandins in the treatment of invasive aspergillosis: A meta-analysis

et al. 2020

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Backgroun /Aim. Although majority of guidelines recommend triazoles (voriconazole, posaconazole, itraconazoleand isavuconazole) as first-line therapeutic option for treatment of invasive aspergillosis, echinocandins (caspofungin, micafungin and anidulafungin) are also used for this purpose. However, head-to-head comparison of triazoles and echinocandins for invasive aspergillosiswas rarely target of clinical trials. The aim of this meta-analysis was to compare efficacy and safety of triazoles and echinocandins when used for treatment of patients with invasive aspergillosis. Methods. This meta-analysis was based on systematic search of literature and selection of high-quality evidence according to pre-set inclusion and exclusion criteria. The literature search was made for comparison of treatment with any of triazoles (isavuconazole, itraconazole, posaconazole or voriconazole) versus any of echinocandins (caspofungin, anidulafungin or micafungin). The effects of triazoles (itraconazole, posaconazole or voriconazole) and echinocandins(caspofungin, anidulafungin or micafungin) were summarized using RevMan 5.3.5 software, and heterogeneity assessed by the Cochrane Q test and I² values. Several types of bias were assessed, and publication bias shown by Funnel plot and Egger's regression. Results. Two clinical trials and three cohort studies were included in this meta-analysis. Mortality in patients with invasive aspergillosis who were treated with triazoles was significantly lower than in patients treated with echinocandins (odds ratio 0.29 [0.13, 0.67]), and rate of favorable response (overall treatment success) 12 weeks after the therapy onset was higher in patients treated with triazoles (3.05 [1.52, 6.13]). On the other hand, incidence of adverse events was higher with triazoles than with echinocandins in patients treated for invasive aspergillosis (3.75 [0.89, 15.76]), although this difference was not significant. Conclusion.Triazoles (voriconazole in the first place) could be considered as more effective and somewhat less safe therapeutic option than echinocandins for invasive aspergillosis; however, due to poor quality of studies included in this meta-analysis definite conclusion should await results of additional, well designed clinical trials.

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“…At our knowledge, posaconazole is not very prone to pharmacogenetic variability due to its low metabolism unlike voriconazole. If voriconazole is substrate and inhibitor of many isoforms of cytochrome P450, posaconazole is an inhibitor but only a weak substrate [ 22 ]. Actually, absorption is clearly the rate-limiting step for pharmacokinetics of posaconazole oral suspension.…”

Section: Discussionmentioning

confidence: 99%

Breakthrough invasive aspergillosis and diagnostic accuracy of serum galactomannan enzyme immune assay during acute myeloid leukemia induction chemotherapy with posaconazole prophylaxis

Calmettes¹,

Gabriel

Blanchard³

et al. 2018

Oncotarget

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Posaconazole prophylaxis has demonstrated efficacy in the prevention of invasive aspergillosis during prolonged neutropenia following acute myeloid leukemia induction chemotherapy. Antifungal treatment decreases serum galactomannan enzyme immunoassay diagnostic accuracy that could delay the diagnosis and treatment.We retrospectively studied patients with acute myeloid leukemia who underwent intensive chemotherapy and antifungal prophylaxis by posaconazole oral suspension. Clinical, radiological, microbiological features and treatment response of patients with invasive aspergillosis that occurred despite posaconazole prophylaxis were analyzed. Diagnostic accuracy of serum galactomannan assay according to posaconazole plasma concentrations has been performed.A total of 288 patients with acute myeloid leukemia, treated by induction chemotherapy, who received posaconazole prophylaxis for more than five days were included in the present study. The incidence of invasive aspergillosis was 8% with 12 (4.2%), 8 (2.8%) and 3 (1%), possible, probable and proven invasive aspergillosis, respectively. Posaconazole plasma concentration was available for 258 patients. Median duration of posaconazole treatment was 17 days, and median posaconazole plasma concentration was 0.5 mg/L. None of patients with invasive aspergillosis and posaconazole concentration ≥ 0.5 mg/L had a serum galactomannan positive test. Sensitivity of serum galactomannan assay to detect probable and proven invasive aspergillosis was 81.8%. Decreasing the cut-off value for serum galactomannan optical density index from 0.5 to 0.3 increased sensitivity to 90.9%.In a homogenous cohort of acute myeloid leukemia patients during induction chemotherapy, increasing the posaconazole concentration decreases the sensitivity of serum galactomannan assay.

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Pharmacogenomics of triazole antifungal agents: implications for safety, tolerability and efficacy

Cited by 47 publications

References 113 publications

Isavuconazole Kinetic Exploration for Clinical Practice

Isavuconazole Kinetic Exploration for Clinical Practice

Efficacy and safety of triazoles versus echinocandins in the treatment of invasive aspergillosis: A meta-analysis

Breakthrough invasive aspergillosis and diagnostic accuracy of serum galactomannan enzyme immune assay during acute myeloid leukemia induction chemotherapy with posaconazole prophylaxis

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