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

Abstract

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.

Figures

Figure 1.

Individual observed posaconazole Cavg following multiple dosing of a posaconazole tablet formulation at 300 mg once daily (serial PK-evaluable population). AM, arithmetic mean; Cavg, average concentration at steady-state.

Figure 2.

Mean (SD) of posaconazole plasma concentration–time profiles by disease state (day 1 and day 8) following multiple dosing of a 300 mg posaconazole tablet formulation once daily (serial PK-evaluable population).

Figure 3.

Individual plot of observed Cavg versus Cmin values on day 8 following multiple dosing of a posaconazole tablet formulation at 300 or 200 mga once daily (n = 68; serial PK-evaluable population). aEighteen patients receiving 200 mg posaconazole were from part 1 of the study; they are included in the regression analysis, but are not further discussed in this paper (results for these patients have been previously presented).

Figure 4.

Individual steady-state posaconazole average Cmin following multiple dosing of a posaconazole tablet formulation at 300 mg once daily (Cmin PK-evaluable cohort). AM, arithmetic mean; Cmin, trough concentration.

Figure 5.

Individual predicted posaconazole Cavg following multiple dosing of a posaconazole tablet formulation at 300 mg once daily (Cmin PK-evaluable population). AM, arithmetic mean; Cavg, average concentration at steady-state.