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

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.

Phase 1b study of new posaconazole tablet for prevention of invasive fungal infections in high-risk patients with neutropenia.

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.).