Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease

Cornely, Oliver A.; Duarte, Rafael F.; Haider, Shariq; Chandrasekar, Pranatharthi H.; Helfgott, David C.; Jiménez, Javier López; Candoni, Anna; Raad, Issam; Laverdière, Michél; Langston, Amelia; Kartsonis, Nicholas A.; Iersel, Marlou Van; Connelly, Nancy; Waskin, Hetty

doi:10.1093/jac/dkv380

Cited by 147 publications

(154 citation statements)

References 20 publications

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“…It is important to note that the primary liver injury observed was hyperbilirubinemia, which is frequently multifactorial in this population and may reflect physiological phenomena rather than drug-induced liver injury (22,23). As a more specific marker of drug-induced liver injury, grade 3 or 4 elevations in ALT levels were observed in only 2% of patients without preexisting liver injury and 5% of patients with such abnormalities, similar to findings observed in the phase 3 clinical trial of PCZ tablets (9). Furthermore, because this was a retrospective study, a cause-effect relationship between serum PCZ levels and liver injury cannot be established or presumed.…”

Section: Discussionsupporting

confidence: 70%

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Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

Tverdek

Heo

Aitken

et al. 2017

Antimicrob Agents Chemother

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Posaconazole is the preferred mold-active azole for prophylaxis against invasive fungal infections (IFIs) in patients with hematological malignancy. Delayedrelease tablet and intravenous formulations of posaconazole have recently become available, but clinical data are limited. We sought to examine the real-world pharmacokinetics and prophylactic effectiveness of the new formulations of posaconazole given as prophylaxis for patients with hematological malignancy. A retrospective cohort of all consecutive adult inpatients with hematological malignancy who received Ն3 days of tablet or intravenous posaconazole therapy for primary IFI prophylaxis at the M. D. Anderson Cancer Center between 1 December 2013 and 31 December 2015 was established. Clinical information was collected and correlated with low posaconazole serum levels (Ͻ700 ng/ml). Rates of IFIs and safety events were assessed. A total of 1,321 courses of posaconazole were administered at the M. D. Anderson Cancer Center during the study period, of which 343 courses were assessed for prophylactic safety and effectiveness. Seventy-nine patients (23%) had posaconazole serum level measurements available for interpretation. Acute myeloid leukemia was the primary malignancy (62%), with 20% of all patients having previously received a stem cell transplant. The median posaconazole level was 1,380 ng/ml (interquartile range, 864 to 1,860 ng/ml). Low posaconazole levels (Ͻ700 ng/ml) were observed for 14 patients (18%). Proven or probable breakthrough IFIs occurred in 8 patients (2%); posaconazole therapeutic drug monitoring (TDM) was performed for 6 of those patients, all with levels above 700 ng/ml. Overall, 19% of patients experienced grade 3 or 4 liver injury, manifesting primarily as hyperbilirubinemia and being correlated with serum levels of Ͼ1,830 ng/ml. Although hepatotoxicity in a small percentage of patients is of concern, posaconazole tablets appeared to be generally safe and effective. As all breakthrough IFIs for which TDM was performed occurred in patients with levels of Ͼ700 ng/ml, and a posaconazole level of Ͼ1,830 ng/ml was correlated with grade 3 or 4 liver toxicity, further studies are needed to assess the role of TDM.KEYWORDS posaconazole, hematological malignancy, prophylaxis, cancer, antifungal I nvasive fungal infections (IFIs) continue to be a significant cause of morbidity and death among patients with hematological malignancy (1). The triazole posaconazole (PCZ) has in vitro, preclinical, and clinical activities against a variety of yeasts and molds (2). Since its introduction 15 years ago, PCZ has been widely used for the prevention and treatment of IFIs in patients with leukemia and in hematopoietic stem cell

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Section: Discussionsupporting

confidence: 70%

“…The tablet and intravenous formulations were approved on the basis of safety and pharmacokinetic data, with corresponding phase III data for the tablet formulation recently being published (9). To date, several small, single-center studies have reviewed the initial implementation of PCZ tablets, focusing mainly on pharmacokinetic endpoints (5,6,(10)(11)(12).…”

mentioning

confidence: 99%

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

Tverdek

Heo

Aitken

et al. 2017

Antimicrob Agents Chemother

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“…54,59 In a recent study, Cornely et al found that 90% of adult patients taking the newer delayed release tablets for prophylaxis of fungal infections had steady-state trough levels >700 ng/mL and there was no correlation between drug levels and adverse events. 60 Thus, TDM is unlikely to provide clinical benefit to patients taking the delayed release formulation of posaconazole for prophylaxis of fungal infections. It is not yet clear whether there will be a role for TDM in patients taking posaconazole for treatment of invasive fungal disease.…”

Section: Isavuconazonium Sulfatementioning

confidence: 99%

New facets of antifungal therapy

et al. 2016

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Invasive fungal infections remain a major cause of morbidity and mortality in immunocompromised patients, and such infections are a substantial burden to healthcare systems around the world. However, the clinically available armamentarium for invasive fungal diseases is limited to 3 main classes (i.e., polyenes, triazoles, and echinocandins), and each has defined limitations related to spectrum of activity, development of resistance, and toxicity. Further, current antifungal therapies are hampered by limited clinical efficacy, high rates of toxicity, and significant variability in pharmacokinetic properties. New antifungal agents, new formulations, and novel combination regimens may improve the care of patients in the future by providing improved strategies to combat challenges associated with currently available antifungal agents. Likewise, therapeutic drug monitoring may be helpful, but its present use remains controversial due to the lack of available data. This article discusses new facets of antifungal therapy with a focus on new antifungal formulations and the synergistic effects between drugs used in combination therapy.

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“…A Phase III multicenter trial used the 300-mg delayed-release posaconazole oral tablet to further examine the pharmacokinetics in AML or myelodysplasia patients along with recent HSCT recipients [30]. During the 28-day trial period, the predefined steady-state concentration goal, set at 0.50–3.75 mg/l, was achieved in 96% of patients, with 81% falling in the range between 0.50 and 2.50 mg/l.…”

Section: Pharmacologymentioning

confidence: 99%

Pharmacologic and clinical evaluation of posaconazole

Moore

Healy

Kraft

2015

Expert Review of Clinical Pharmacology

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Posaconazole, a broad-spectrum triazole antifungal agent, is approved for the prevention of invasive aspergillosis and candidiasis in addition to the treatment of oropharyngeal candidiasis. There is evidence of efficacy in the treatment and prevention of rarer, more difficult-to-treat fungal infections. Posaconazole oral suspension solution has shown limitations with respect to fasting state absorption, elevated gastrointestinal pH and increased motility. The newly approved delayed-release oral tablet and intravenous solution formulations provide an attractive treatment option by reducing interpatient variability and providing flexibility in critically ill patients. On the basis of clinical experience and further clinical studies, posaconazole was found to be a valuable pharmaceutical agent for the treatment of life-threatening fungal infections. This review will examine the development history of posaconazole and highlight the most recent advances.

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Phase 3 pharmacokinetics and safety study of a posaconazole tablet formulation in patients at risk for invasive fungal disease

Cited by 147 publications

References 20 publications

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

Real-Life Assessment of the Safety and Effectiveness of the New Tablet and Intravenous Formulations of Posaconazole in the Prophylaxis of Invasive Fungal Infections via Analysis of 343 Courses

New facets of antifungal therapy

Pharmacologic and clinical evaluation of posaconazole

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