A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers

Abstract

ObjectivesPosaconazole 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.MethodsThis 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).ResultsAfter 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 Tmax 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. Cavg 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.ConclusionsPosaconazole 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.

Challenges and Strategies in Thermal Processing of Amorphous Solid Dispersions: A Review

“…The Meltrex® platform commercialized by Soliqs and AbbVie is perhaps the most well-known example of HME-enabled products in the pharmaceutical industry, including the solid oral dosage forms of Kaletra® and Norvir® for treatment of HIV (34), the recently approved Viekirax® for treatment of HCV (35,36), and other products in development for oncology indications (37). In addition, other pharmaceutical companies have adopted hot-melt extrusion technology with the recent approvals of Onmel® by Merz Pharmaceuticals and Noxafil® by Merck & Co (38)(39)(40). Despite this recent commercial success of HME for pharmaceutical applications, a number of challenges still exist, particularly for thermally labile drugs and polymers, as well as viscosity limitations for a number of pharmaceutical polymer carriers.…”

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

“…and delayed-release (DR) tablet formulations of PCZ result in significantly higher serum PCZ concentrations and increased attainment of traditional pharmacokinetic targets, compared to the PCZ suspension (5,6). Additionally, the DR formulation has been demonstrated to provide more consistent absorption and is minimally affected by gastric pH and motility (7,8). At the M. D. Anderson Cancer Center (MDACC), patients with hematological malignancy were nearly universally transitioned from PCZ suspension to DR tablets; the i.v.…”

Posaconazole Tablet Formulation at 400 Milligrams Daily Achieves Desired Minimum Serum Concentrations in Adult Patients with a Hematologic Malignancy or Stem Cell Transplant

“…Though limited by a small sample size and one-arm design, our data suggest that increasing the dose of PTF from 300 to 400 mg daily is a reasonable intervention to achieve the desired minimum serum concentrations in patients unable to achieve the aforementioned target trough concentrations while receiving the 300-mg daily dosing. The 33% dose change (300 to 400 mg) resulted in a disproportionate 81.8% (0.55 to 1.00 g/ml) increase in median trough concentration that may be explained by the compounded effect of "loading" the patient on 300 mg daily and then 400 mg daily in a single cohort; the other dose-escalation studies compared different doses in multiple cohorts (6,7). The increased dose did not appear to incur additional hepatotoxicity or QTc prolongation.…”