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The triazole antifungal posaconazole was first approved as an oral suspension formulation. Despite pharmacokinetic target attainment and clinical efficacy in premarketing trials, postmarketing analyses indicated unpredictable bioavailability resulting in subtherapeutic concentrations and reports of breakthrough fungal infections. The newly approved posaconazole delayed-release tablet and intravenous formulations display more consistent bioavailability in the presence of concomitant disease states, medications, and dietary considerations that classically alter drug concentrations of the oral suspension. Both the delayed-release tablet and intravenous formulation display a similar adverse-effect profile to the oral suspension. The posaconazole delayed-release oral tablet is not significantly affected by gastric acid suppression therapy, and the intravenous dosage form provides an option for patients who are intubated or unable to tolerate oral medications. Pharmacoeconomic considerations, particularly with intravenous posaconazole, will likely play a role in dosage form selection and frequency of use. Due to sustained, higher drug concentrations, the new posaconazole formulations hold promise for greater efficacy in antifungal prophylaxis and bring opportunity for further study in the treatment of invasive mycoses. [ABSTRACT FROM AUTHOR]

Abstract: Posaconazole (PCZ) is approved for fungal prophylaxis in high-risk neutropenic patients. Unfortunately, PCZ oral absorption is affected by nutritional intake and drug interactions with proton pump inhibitors (PPIs) and possibly histamine-2 antagonists (H2As). Cancer patients frequently receive stress ulcer prophylaxis (SUP) with PPIs or H2As. Recommended PCZ steady-state concentrations (C ss) are difficult to achieve using the traditional dosing regimen of 200mg thrice daily. Given the paucity of guidance on PCZ dosing in patients receiving SUP, this study evaluated attainment of targeted PCZ C ss (0.5μg/mL and 0.7μg/mL) with two different PCZ dosing regimens when SUP was given. Twenty patients received the traditional dosing and 34 patients received 400mg twice daily. Median PCZ C ss levels were 0.37μg/mL and 0.32μg/mL with the traditional and 400mg twice-daily regimens, respectively (P =0.809). When stratified by type of SUP, H2A patients had a median PCZ C ss of 0.39μg/mL, whereas PPI patients had a median PCZ C ss of 0.32μg/mL. Despite having more patients with PCZ C ss >0.5μg/mL in the H2A group, a statistical significance was not found (P =0.368). Multiple logistic regression did show that increasing age [odds ratio (OR)=1.08, 95% confidence interval (CI) 1.03–1.19] and use of H2As over PPIs (OR=6.8, 95% CI 1.22–55.16] was associated with PCZ target attainment. These results suggest that PCZ target attainment is similar with either PCZ regimen but that there may be less of an interaction with H2As compared with PPIs. [Copyright &y& Elsevier]

Abstract: This is one of the first studies to report on therapeutic drug monitoring (TDM) of posaconazole (PCZ) for antifungal prophylaxis in patients with acute myelogenous leukaemia or myelodysplastic syndrome outside of the rigours of clinical licencing trials. A number of factors have been identified or proposed as causing poor oral absorption of PCZ. Putative PCZ concentrations have been recommended for TDM (0.5μg/mL or 0.7μg/mL). In this study, 19 (90.5%) of 21 patients failed to reach the higher putative target of 0.7μg/mL, and 16 patients (76.2%) failed to reach the lower target of 0.5μg/mL. Increasing the dose did not help four of six patients reach target concentrations. Three of the patients developed ‘proven’ or ‘possible’ fungal infections, all with PCZ concentrations <0.5μg/mL. Use of acid-suppressing agents appears to explain some of the poor absorption. TDM of PCZ is warranted in patients receiving this orally administered agent. [Copyright &y& Elsevier]