A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients

Thakuria, Louit; Packwood, Kerri; Firouzi, Ashi; Rogers, Paula; Soresi, Simona; Habibi-Parker, Kirsty; Lyster, Haifa; Zych, Bartłomiej; Garcia-Saez, Diana; Mohite, Prashant N.; Patil, Nikhil P.; Sabashnikov, Anton; Capoccia, Massimo; Chibvuri, Molly; Lamba, Harpal; Tate, H.; Carby, Martin; Simón, A.; Leaver, Neil; Reed, Anna

doi:10.1016/j.ijantimicag.2015.09.015

Cited by 14 publications

(10 citation statements)

References 27 publications

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“…In a second study of 20 lung transplant recipients by the same authors group, posaconazole concentration were slightly lower: C max was 1.3 µg/mL in ELF, 1.3 µg/mL in plasma, and 55.4 µg/mL in alveolar cells [ 260 ]. During the perioperative period, highly variable levels were measured in bronchoalveolar lavage fluid of transplant recipients on prophylaxis with posaconazole oral suspension [ 261 ].…”

Section: Posaconazolementioning

confidence: 99%

Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients

2017

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IntroductionBecause of the high mortality of invasive fungal infections (IFIs), appropriate exposure to antifungals appears to be crucial for therapeutic efficacy and safety.Materials and methodsThis review summarises published pharmacokinetic data on systemically administered antifungals focusing on co-morbidities, target-site penetration, and combination antifungal therapy.Conclusions and discussionAmphotericin B is eliminated unchanged via urine and faeces. Flucytosine and fluconazole display low protein binding and are eliminated by the kidney. Itraconazole, voriconazole, posaconazole and isavuconazole are metabolised in the liver. Azoles are substrates and inhibitors of cytochrome P450 (CYP) isoenzymes and are therefore involved in numerous drug–drug interactions. Anidulafungin is spontaneously degraded in the plasma. Caspofungin and micafungin undergo enzymatic metabolism in the liver, which is independent of CYP. Although several drug–drug interactions occur during caspofungin and micafungin treatment, echinocandins display a lower potential for drug–drug interactions. Flucytosine and azoles penetrate into most of relevant tissues. Amphotericin B accumulates in the liver and in the spleen. Its concentrations in lung and kidney are intermediate and relatively low myocardium and brain. Tissue distribution of echinocandins is similar to that of amphotericin. Combination antifungal therapy is established for cryptococcosis but controversial in other IFIs such as invasive aspergillosis and mucormycosis.

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Section: Posaconazolementioning

confidence: 99%

Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients

2017

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“…Conversely, the oral tablet form of posaconazole provides better pharmacokinetics compared with the oral suspension. Therapeutic drug monitoring to document an acceptable systemic itraconazole, posaconazole, and voriconazole levels is generally recommended, 29 but the optimal trough level that is needed for prophylactic efficacy has not been defined. Drug doses, therefore, vary depending on center-specific practices.…”

Section: Preventionmentioning

confidence: 99%

Fungal Infections After Lung Transplantation

Kennedy

Razonable

2017

Clinics in Chest Medicine

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“…Posaconazole was initially approved as an oral suspension by the U.S. Food and Drug Administration in 2006, and subsequently as a sustained-release tablet and intravenous formulation in 2013 and 2014, respectively. Despite nearly a decade of clinical experience with posaconazole, there remains a paucity of pharmacokinetic and clinical data among LTRs (8,9), particularly among patients with cystic fibrosis (CF), which is a major indication for lung transplantation.…”

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confidence: 99%

“…Achieving therapeutic concentrations of posaconazole is especially challenging for CF patients given populationspecific factors such as poor oral absorption, a larger volume of distribution, and an increased clearance of certain drugs. Unfortunately, the pharmacokinetics of posaconazole oral suspension have been reported only in a limited number of patients with CF (8,9). The administration of posaconazole as a sustained-release tablet results in improved pharmacokinetics among patients with hematological malignancy (12,13); however, no data are available among LTRs.…”

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confidence: 99%

Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

Zhang

Nguyen

Clancy

et al. 2016

Antimicrob Agents Chemother

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dInvasive fungal infections (IFIs) are common among lung transplant recipients (LTRs). Posaconazole is an important antifungal agent for both prophylaxis and treatment of IFIs; however, detailed pharmacokinetic data are limited among LTRs, particularly those with cystic fibrosis (CF). Our objective was to conduct a pharmacokinetic study of posaconazole oral suspension among LTRs, with particular attention to patients with CF. We enrolled 20 LTRs, 7 with CF and 13 with other underlying lung diseases. Average daily doses in CF and non-CF patients were 829 and 862 mg, respectively. After >5 days of treatment, only 4 patients had average plasma concentrations of >0.7 g/ml. Average steady-state plasma concentrations were 61% lower in CF patients (0.233 g/ml) than in non-CF LTRs (0.594 g/ml; P ‫؍‬ 0.03). The average dose-normalized plasma area-under-the-curve (AUC) values were also lower in CF (0.007 h·g/ml) than in non-CF LTRs (0.02 h·g/ml; P ‫؍‬ 0.02). The weight-normalized apparent oral clearance values were 2.51 and 0.74 liters/h/kg among CF and non-CF LTRs, respectively (P ‫؍‬ 0.005). Despite significant interpatient variability, plasma trough concentrations were strongly correlated with posaconazole AUC across all LTRs (r 2 ‫؍‬ 0.95, P < 0.0001). Taken together, our study highlights a critical need to incorporate new formulations of posaconazole into prophylaxis and treatment strategies for LTRs, particularly those with CF. Future pharmacokinetic studies of both tablet and intravenous formulations must consider LTR-specific factors and incorporate a therapeutic drug monitoring plan in this patient population.

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A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients

Cited by 14 publications

References 27 publications

Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients

Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients

Fungal Infections After Lung Transplantation

Pharmacokinetics of Posaconazole Suspension in Lung Transplant Patients with and without Cystic Fibrosis

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