Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations

Märtson, Anne-Grete; Veringa, Anette; Heuvel, Edwin R. van den; Bakker, M.; Touw, Daan; Werf, Tjip S van der; Span, Lambert F.R.; Alffenaar, Jan-Willem

doi:10.1111/myc.12948

Cited by 17 publications

(10 citation statements)

References 42 publications

(59 reference statements)

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“…The univariate and multiple linear regression analysis both showed that lower PCZ concentrations were observed with decreasing albumin concentrations, which is in line with previous analysis ( Märtson et al, 2019b ; Sime et al, 2019 ). Although CRP level in the current study was negatively correlated with PCZ C min in the univariate analysis, multiple linear regression analysis did not reveal any statistically significant association, which is consistent with the findings of Märtson et al (2019a) .…”

Section: Discussionsupporting

confidence: 91%

“…However, no such association was observed in our hematological disorders patient. Although PCZ treatment is associated with liver function abnormalities ( Boglione-Kerrien et al, 2018 ), the effect of liver function on PCZ concentrations was not confirmed in our study, which is consistent with the results previously published by Märtson et al (2019b) . Collectively, these results indicate that it is difficult to predict PCZ concentration that we have to monitor trough concentration and adjust PCZ dosage according to the results.…”

Section: Discussionsupporting

confidence: 77%

“…Additionally, we also investigated factors contributing to dose-normalized PCZ concentration variability. Dose-normalized PCZ concentrations were reported instead of actual concentrations to take into account the large variations in PCZ daily doses used when the samples were obtained ( Allegra et al, 2017 ; Jeong et al, 2018 ; Märtson et al, 2019b ). By using this measure, the estimated values could be compared within and between patients without taking variations in the dosage into consideration.…”

Section: Discussionmentioning

confidence: 99%

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Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders

et al. 2020

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Posaconazole (PCZ) is effective in preventing and salvage treatment invasive fungal infections in patients with hematologic disorders. However, PCZ displays highly variable individual pharmacokinetics affecting its efficacy and safety. To investigate the correlation between PCZ concentration and efficacy and safety, the following key influencing factors were explored. A total of 285 trough plasma concentrations (C min ) of 81 Chinese patients receiving PCZ oral suspension for prophylaxis or treatment of invasive fungal infections were collected in this study. The relationships between C min values and clinical response and hepatotoxicity were investigated as well as the incidence of clinical response under different C min values of PCZ with a logistic regression model. The concentration of PCZ showed remarkable differences among patients with haematologic disorders. PCZ C min values of 0.76 and 1.0 µg/mL were both associated with an over 80% probability of successful response to prophylaxis and treatment of fungal infections, respectively. No association between C min values and hepatotoxicity was noted ( P > 0.05). Gender, albumin, and co-administration of proton pump inhibitor (PPI) were identified as independent factors influencing PCZ C min by multiple linear regression analysis. Furthermore, patients’ C-reactive protein (CRP), albumin, and co-administration of PPI exhibited significant effects on the therapeutic window of patients receiving PCZ for prophylaxis. The plasma concentration is closely associated with therapeutic efficacy of PCZ. It is necessary to adjust the dosing regimens based on PCZ C min to obtain an optimal therapeutic response.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders

et al. 2020

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“…105 However, higher posaconazole concentrations are not uncommon. 187,188,190,195,198,199 Although the drug is well tolerated, dose reduction should be considered if adverse drug effects occur and the posaconazole concentration is >2.5 mg/L, with follow-up TDM recommended. As there is no established clear threshold concentration for toxicity, a caseby-case approach is suggested.…”

Section: Question 2 What Are the Present Antifungal Tdm Targets Sampling And Sample Type Time-to-resampling And Dose Adjustment?mentioning

confidence: 99%

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021

Chau

Daveson

Alffenaar

et al. 2021

Internal Medicine Journal

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Antifungal agents can have complex dosing and the potential for drug interaction, both of which can lead to subtherapeutic antifungal drug concentrations and poorer clinical outcomes for patients with haematological malignancy and haemopoietic stem cell transplant recipients. Antifungal agents can also be associated with significant toxicities when drug concentrations are too high. Suboptimal dosing can be minimised by clinical assessment, laboratory monitoring, avoidance of interacting drugs, and dose modification. Therapeutic drug monitoring (TDM) plays an increasingly important role in antifungal therapy, particularly for antifungal agents that have an established exposure-response relationship with either a narrow therapeutic window, large dose-exposure variability, cytochrome P450 gene polymorphism affecting drug metabolism, the presence of antifungal drug interactions or unexpected toxicity, and/or concerns for non-compliance or inadequate absorption of oral antifungals. These guidelines provide recommendations on antifungal drug monitoring and TDM-guided dosing adjustment for selected antifungal agents, and include suggested resources for identifying and analysing antifungal drug interactions. Recommended competencies for optimal interpretation of antifungal TDM and dose recommendations are also provided.

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“…Pharmacological advice on drug adjustment was applied only partially, due to a borderline concentration or overexposure without toxicity. 314 High-dose PSZ treatment (300 mg •2) with a target trough level .3 mg/L and spontaneous drug levels .3 mg/ L are associated with potential hepatic or cardiac safety issues requiring close monitoring. However, drug intensification is feasible with TDM and clinical surveillance.…”

Section: Psz Tabletsmentioning

confidence: 99%

Antifungal Drugs TDM: Trends and Update

Kably

Launay

Derobertmasure

et al. 2022

Therapeutic Drug Monitoring

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The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. Methods:We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-druginteraction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure.Results: More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available.Conclusions: TDM seems to be crucial for curative and/or longterm maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

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Posaconazole therapeutic drug monitoring in clinical practice and longitudinal analysis of the effect of routine laboratory measurements on posaconazole concentrations

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Cited by 17 publications

References 42 publications

Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders

Deciphering the Relationship Between the Trough Concentration of Posaconazole and Its Efficacy and Safety in Chinese Patients With Hematological Disorders

Consensus guidelines for optimising antifungal drug delivery and monitoring to avoid toxicity and improve outcomes in patients with haematological malignancy and haemopoietic stem cell transplant recipients, 2021

Antifungal Drugs TDM: Trends and Update

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