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Objectives: The association of posaconazole serum concentrations and toxicity is unclear. An assessment of whether levels obtained with the delayed-release tablet (DRT) formulation are correlated with abnormal liver function test (LFT) results and/or QTc prolongation was undertaken., Methods: This was a multicentre, retrospective, observational study of adult patients with cancer between 26 November 2013 and 14 November 2014. Patients were included if they received posaconazole DRT with a posaconazole level obtained between days 5 and 14. Clinical data, including demographics, hepatotoxic medications, posaconazole levels, LFTs and QTc intervals, were obtained. Association of factors with changes in LFTs and QTc prolongation was assessed using linear and logistic regression., Results: One hundred and sixty-six study patients were included. The median posaconazole level was 1250 (range 110-4220) ng/mL and the median time until level was 6 (range 5-14) days. There was a statistically significant increase in AST ( P  <   0.001), ALT ( P  <   0.001), alkaline phosphatase (ALK) ( P  <   0.001), total bilirubin (TBILI) ( P  <   0.001) and QTc ( P  =   0.05) from baseline. Posaconazole levels were not associated with increases in AST [β (SE) = -0.33 (2.2), P  =   0.88], log ALT [β (SE) = -0.02 (0.03), P  =   0.63], ALK [β (SE) = 2.2 (2.9), P  =   0.46] and TBILI [β (SE) = -0.01 (0.04), P  =   0.88]. For each additional hepatotoxic medication, there was a mean change in TBILI of 0.13 mg/dL ( P  =   0.02) and ALK of 7.1 U/L ( P  =   0.09). No statistically significant association between posaconazole level and QTc interval prolongation was found., Conclusions: 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., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Antifungal prophylaxis with a new oral tablet formulation of posaconazole may be beneficial to patients at high risk for invasive fungal disease. A two-part (Phase 1B/3) study evaluated posaconazole tablet pharmacokinetics (PK) and safety., Methods: Patients with neutropenia following chemotherapy for haematological malignancy or recipients of allogeneic HSCT receiving prophylaxis or treatment for graft-versus-host disease received 300 mg posaconazole (as tablets) once daily (twice daily on day 1) for up to 28 days without regard to food intake. Weekly trough PK sampling was performed during therapy, and a subset of patients had sampling on days 1 and 8. Cmin-evaluable subjects received ≥6 days of dosing, and were compliant with specified sampling timepoints. Steady-state PK parameters, safety, clinical failure and survival to day 65 were assessed. ClinicalTrials.gov, NCT01777763; EU Clinical Trials Register, EUDRA-CT 2008-006684-36., Results: Two hundred and ten patients received 300 mg posaconazole (as tablets) once daily. Among Cmin-evaluable subjects (n = 186), steady-state mean Cmin was 1720 ng/mL (range = 210-9140). Steady-state Cmin was ≥700 ng/mL in 90% of subjects with 5% (10 of 186) <500 ng/mL and 5% (10 of 186) 500-700 ng/mL. Six (3%) patients had steady-state Cmin ≥3750 ng/mL. One patient (<1%) had an invasive fungal infection. The most common treatment-related adverse events were nausea (11%) and diarrhoea (8%). There was no increase in adverse event frequency with higher posaconazole exposure., Conclusions: In patients at high risk for invasive fungal disease, 300 mg posaconazole (as tablets) once daily was well tolerated and demonstrated a safety profile similar to that reported for posaconazole oral suspension: most patients (99%) achieved steady-state pCavg exposures >500 ng/mL and only one patient (<1%) had a pCavg <500 ng/mL., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We evaluated posaconazole serum concentrations and hepatotoxicity in 12 leukemia patients who transitioned from posaconazole suspension to tablets. Patients who switched to tablets had significantly increased posaconazole concentrations (median: suspension, 748 ng/ml; tablet, 1,910 ng/ml; P < 0.01) without clinically relevant hepatotoxicity., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Posaconazole tablets, a new oral formulation of posaconazole, can be effective when given as antifungal prophylaxis to neutropenic patients at high risk for invasive fungal infection (e.g., those with acute myelogenous leukemia or myelodysplastic syndrome). Such effectiveness might be specifically important to patients with poor oral intake because of nausea, vomiting, or chemotherapy-associated mucositis. This was a prospective, global study in high-risk patients to characterize the pharmacokinetics and safety profile of posaconazole tablets and to identify the dose of posaconazole tablets that would provide exposure within a predefined range of exposures (steady-state average concentration [area under the concentration-time curve/24 h] of ≥500 ng/ml and ≤2,500 ng/ml in >90% of patients). The study evaluated two sequential dosing cohorts: 200 mg posaconazole once daily (n = 20) and 300 mg posaconazole once daily (n = 34) (both cohorts had a twice-daily loading dose on day 1) taken without regard to food intake during the neutropenic period for ≤28 days. The exposure target was reached (day 8) in 15 of 19 (79%) pharmacokinetic-evaluable patients taking 200 mg posaconazole once daily and in 31 of 32 (97%) patients taking 300 mg posaconazole once daily; 300 mg posaconazole once daily achieved the desired exposure target. Posaconazole tablets were generally well tolerated in high-risk neutropenic patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01777763.)., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Objectives: Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet., Methods: This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18-65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo)., Results: After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median T(max) of 4-5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ∼3 for 200 and 400 mg once daily and ∼5 for 200 mg twice daily. C(avg) values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients., Conclusions: Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections.

Oropharyngeal candidiasis (OPC) is among the most common opportunistic infections observed in persons infected with human immunodeficiency virus. A once-daily miconazole 50 mg mucoadhesive buccal tablet (MBT) is a novel delivery system with potent in vitro activity against many Candida species, including some that may be resistant to other azoles. MBT, although more expensive, offers an effective, safe, and well-tolerated topical treatment option for OPC that is administered as a convenient once-daily dose.

Oropharyngeal candidiasis is a commonly encountered problem in daily clinical practice. Topical therapies for oropharyngeal candidiasis are considered preferable to systemic therapies in most patient populations. However, traditional topical therapies have limitations including short contact time with the oral mucosa and the need for multiple doses each day. Miconazole mucoadhesive tablet has recently been approved in Europe (Loramyc®) and the USA (Oravig™) for the treatment of oropharyngeal candidiasis. This tablet adheres to the oral mucosa and provides sustained local release of miconazole over a period of several hours with just one daily application. This article reviews the pharmacology, safety and efficacy of this novel agent.