Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation

Pettit, Natasha N; Miceli, Marisa H.; Rivera, Christina G.; Narayanan, Prasanna P.; Perissinotti, Anthony J.; Hsu, Meier; Delacruz, Jennifer; Gedrimaite, Zivile; Han, Zhe; Steinbeck, Jennifer L.; Pisano, Jennifer; Seo, Susan K.; Paskovaty, Alla

doi:10.1093/jac/dkx122

Cited by 31 publications

(21 citation statements)

References 9 publications

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“…Some studies indicated that the incidences of LFT abnormalities are generally transient and reversible for long-term posaconazole use [2,108,109]. Most studies found no correlation between posaconazole exposure and hepatotoxicity occurrence [107,[110][111][112]. Nevertheless, in 343 hematological patients receiving delayed-release tablets or intravenous injections, a posaconazole concentration of > 1.83 mg/L was proven to be correlated with grade 3/4 hepatotoxicity using classification and regression-tree analysis, although no association was found using logistic regression [113].…”

Section: Hepatotoxicitymentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Posaconazole

Chen

Krekels

Verweij

et al. 2020

Drugs

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Posaconazole is typically used for preventing invasive yeast and mold infections such as invasive aspergillosis in high-risk immunocompromised patients. The oral suspension was the first released formulation and many pharmacokinetic and pharmacodynamic studies of this formulation have been published. Erratic absorption profiles associated with this formulation were widely reported. Posaconazole exposure was found to be significantly influenced by food and many gastrointestinal conditions, including pH and motility. As a result, low posaconazole plasma concentrations were obtained in large groups of patients. These issues of erratic absorption urged the development of the subsequently marketed delayed-release tablet, which proved to be associated with higher and more stable exposure profiles. Shortly thereafter, an intravenous formulation was released for patients who are not able to take oral formulations. Both new formulations require a loading dose on day 1 to achieve high posaconazole concentrations more quickly, which was not possible with the oral suspension. So far, there appears to be no evidence of increased toxicity correlated to the higher posaconazole exposure achieved with the regimen for these formulations. The higher systemic availability of posaconazole for the delayed-release tablet and intravenous formulation have resulted in these two formulations being preferable for both prophylaxis and treatment of invasive fungal disease. This review aimed to integrate the current knowledge on posaconazole pharmacokinetics, pharmacodynamics, major toxicity, existing resistance, clinical experience in special populations, and new therapeutic strategies in order to get a clear understanding of the clinical use of this drug.

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Section: Hepatotoxicitymentioning

confidence: 99%

“…There are less safety concerns with respect to prolonged QT or QTc in patients with persistent febrile neutropenia or refractory IFD, patients with chronic pulmonary aspergillosis, and lung transplant patients [105][106][107]. No discernable correlation between posaconazole exposure and cardiotoxicity has been found to date [30,110].…”

Section: Cardiotoxicitymentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Posaconazole

Chen

Krekels

Verweij

et al. 2020

Drugs

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“…In the phase 3 study of the delayed-release tablet POS, C min from 0.5 to 3.75 mg/L was considered to be safe [1]. Moreover, recent studies failed to demonstrate any link between the POS C min and toxicity [12,14,30], even if some authors reported some cases of adverse events in patients with a POS C min > 1.8 mg/L [9,31,32]. Finally, although our results suggest that a gain of antifungal activity can be expected until a POS C min of 4.8 mg/L, additional research is needed to determine whether such POS exposure significantly improves efficacy without inducing toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…The new tablet formulation makes it possible to reach higher POS C min values than for the oral suspension [6][7][8]. This greater POS C min could theoretically result in a greater risk of side effects, although no study has yet clearly highlighted increased toxicity with the POS tablet formulation [2,[9][10][11][12][13][14]. Hence, no upper threshold for the POS C min has yet been proposed, even if some authors have suggested that dose reduction could be feasible for at least half of patients [15,16].…”

Section: Introductionmentioning

confidence: 99%

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Willeman¹,

Tonini²,

Garnaud

et al. 2019

Fundamemntal Clinical Pharma

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Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (Cmin) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper Cmin threshold has been yet proposed. We aimed to investigate the pharmacokinetic–pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic Cmin of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal Cmin were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis–Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS Cmin corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS Cmin and a lower threshold of 2.0 mg/L for the Cmin of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target Cmin of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).

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“…Real-life studies have shown suboptimal posaconazole exposure with tablet or IV formulation was associated with very low rates of breakthrough IFI (0.0–6.7%) [ 44 , 48 ]. In addition, there is no association between increasing posaconazole exposure and liver injury or QTc prolongation [ 49 ]. Overall, Lewis considered that TDM for posaconazole could be useful because the azole shows substantial PK variability and the therapeutic window in humans is well defined, but he noted that whether or not the drug has a narrow therapeutic window is not clear.…”

Section: Timing Of Ifi Riskmentioning

confidence: 99%

Invasive Fungal Infections in High-Risk Patients: Report from TIMM-8 2017

Pagano

Mayor

2018

Future Sci. OA

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Trends in Medical Mycology (TIMM) is the biennial meeting of the Infectious Disease Group of the European Organisation for Research and Treatment of Cancer (EORTC) and the European Confederation of Medical Mycology (ECMM). It brings together clinicians and researchers from across the world to share the latest R&Ds in medical mycology. Despite advances in treatment, invasive fungal infections remain a major cause of morbidity and mortality in certain high-risk groups of patients, particularly in immunocompromised patients, including those undergoing solid organ transplantation and those with acute leukemia. The challenges for clinicians are now compounded by the rapid development of multidrug resistance. The latest data and approaches to identifying patients at high risk for invasive fungal infections, ensuring early diagnosis and achieving effective treatment, including when and how to use therapeutic drug monitoring with azoles, were shared with >1000 clinicians and researchers from around the world attending the eighth TIMM, held in Belgrade, Serbia, in October 2017 (TIMM-8 2017).

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Multicentre study of posaconazole delayed-release tablet serum level and association with hepatotoxicity and QTc prolongation

Abstract: We did not identify an association between posaconazole serum concentrations and LFT elevations or QTc prolongation. However, some LFTs were found to increase with more hepatotoxic medications administered.

Cited by 31 publications

References 9 publications

Pharmacokinetics and Pharmacodynamics of Posaconazole

Pharmacokinetics and Pharmacodynamics of Posaconazole

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Invasive Fungal Infections in High-Risk Patients: Report from TIMM-8 2017

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