Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

Blennow, Ola; Eliasson, Erik; Pettersson, Tommy; Pohanka, Anton; Szakos, Attila; El-Serafi, Ibrahim; Hassan, Manal M.; Ringdén, Olle; Mattsson, Jonas

doi:10.1128/aac.03252-14

Cited by 21 publications

(14 citation statements)

References 15 publications

(17 reference statements)

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“…A more recently approved delayed-release oral tablet could reduce inter-patient variability and can be taken once daily without the need for food intake to support adequate absorption [73,74]. Data concerning posaconazole diffusion into the brain are limited [75,76], although efficacy when treating invasive cerebral fungal infections have been reported in murine models [77] and clinical cases reports, suggesting that it crosses the blood brain barrier in sufficient quantities to treat cerebral fungal infection and thus possibly treat late stage sleeping sickness [78–80]. The recent results in a phase II clinical trial with posaconazole for Chagas disease have been disappointing [81].…”

Section: Discussionmentioning

confidence: 99%

Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model

Dauchy¹,

Bonhivers²,

Landrein³

et al. 2016

PLoS Negl Trop Dis

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Trypanosoma brucei gambiense is the main causative agent of Human African Trypanosomiasis (HAT), also known as sleeping sickness. Because of limited alternatives and treatment toxicities, new therapeutic options are urgently needed for patients with HAT. Sterol 14alpha-demethylase (CYP51) is a potential drug target but its essentiality has not been determined in T. brucei. We used a tetracycline-inducible RNAi system to assess the essentiality of CYP51 in T. brucei bloodstream form (BSF) cells and we evaluated the effect of posaconazole, a well-tolerated triazole drug, within a panel of virulent strains in vitro and in a murine model. Expression of CYP51 in several T. brucei cell lines was demonstrated by western blot and its essentiality was demonstrated by RNA interference (CYP51RNAi) in vitro. Following reduction of TbCYP51 expression by RNAi, cell growth was reduced and eventually stopped compared to WT or non-induced cells, showing the requirement of CYP51 in T. brucei. These phenotypes were rescued by addition of ergosterol. Additionally, CYP51RNAi induction caused morphological defects with multiflagellated cells (p<0.05), suggesting cytokinesis dysfunction. The survival of CYP51RNAi Doxycycline-treated mice (p = 0.053) and of CYP51RNAi 5-day pre-induced Doxycycline-treated mice (p = 0.008) were improved compared to WT showing a CYP51 RNAi effect on trypanosomal virulence in mice. The posaconazole concentrations that inhibited parasite growth by 50% (IC50) were 8.5, 2.7, 1.6 and 0.12 μM for T. b. brucei 427 90–13, T. b. brucei Antat 1.1, T. b. gambiense Feo (Feo/ITMAP/1893) and T. b. gambiense Biyamina (MHOM/SD/82), respectively. During infection with these last three virulent strains, posaconazole-eflornithine and nifurtimox-eflornithine combinations showed similar improvement in mice survival (p≤0.001). Our results provide support for a CYP51 targeting based treatment in HAT. Thus posaconazole used in combination may represent a therapeutic alternative for trypanosomiasis.

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Section: Discussionmentioning

confidence: 99%

Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model

Dauchy¹,

Bonhivers²,

Landrein³

et al. 2016

PLoS Negl Trop Dis

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“…The concentrations determined at autopsy were 520 mg/kg in cardiac muscle and 16.7 mg/l in femoral blood [131]. The accumulation in cardiac tissue was also suggested for posaconazole which had reached the concentration in heart tissue up to 18 times higher than in plasma (the mean ratio for seven cadavers was 8.4) [68]. Likewise, α-tocopherol levels in the heart of two autopsy patients who had been supplemented with vitamin E before death, exceeded those in plasma [78].…”

Section: Othersmentioning

confidence: 85%

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Tylutki

Polak

2015

Biopharm & Drug Disp

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ABSTRACT:Little is known about the uptake of drugs into the human heart, although it is of great importance nowadays, when science desires to predict tissue level behavior rather than to measure it. Although the drug concentration in cardiac tissue seems a better predictor for physiological and electrophysiological changes than its level in plasma, knowledge of this value is very limited. Tissue to plasma partition coefficients (Kp) come to rescue since they characterize the distribution of a drug among tissues as being one of the input parameters in physiologically based pharmacokinetic (PBPK) models. The article reviews cardiac surgery and forensic medical studies to provide a reference for drug concentrations in human cardiac tissue. Firstly, the focus is on whether a drug penetrates into heart tissue at a therapeutic level; the provided values refer to antibiotics, antifungals and anticancer drugs. Drugs that directly affect cardiomyocyte electrophysiology are another group of interest. Measured levels of amiodarone, digoxin, perhexiline and verapamil in different sites in human cardiac tissue where the compounds might meet ion channels, gives an insight into how these more lipophilic drugs penetrate the heart. Much data are derived from postmortem studies and they provide insight to the cardiac distribution of more than 200 drugs. The analysis depicts potential problems in defining the active concentration location, what may indirectly suggest multiple mechanisms involved in the drug distribution within the heart.

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“…This pattern was not observed in the delayed-release tablet [28] due to the distinct differences in the gastrointestinal drug-delivery features between these two oral formulations. Figure 2 shows posaconazole distribution in various human tissues and fluids after systemic administration [52][53][54][55][56][57][58][59][60][61]. This figure shows that posaconazole accumulates in peripheral tissues, especially in lungs, kidneys, liver, and heart [52,62].…”

Section: Absorptionmentioning

confidence: 99%

“…Figure 2 shows posaconazole distribution in various human tissues and fluids after systemic administration [52][53][54][55][56][57][58][59][60][61]. This figure shows that posaconazole accumulates in peripheral tissues, especially in lungs, kidneys, liver, and heart [52,62]. For instance, exposure in alveolar cells is about 32-fold higher than in plasma, although the exposure in the pulmonary epithelial lining fluid (ELF) is slightly lower than in plasma in healthy volunteers receiving the 400 mg posaconazole suspension BID [54].…”

Section: Absorptionmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Posaconazole

Chen

Krekels

Verweij

et al. 2020

Drugs

107

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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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Posaconazole Concentrations in Human Tissues after Allogeneic Stem Cell Transplantation

Cited by 21 publications

References 15 publications

Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model

Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model

Plasma vs heart tissue concentration in humans – literature data analysis of drugs distribution

Pharmacokinetics and Pharmacodynamics of Posaconazole

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