Treatment by Posaconazole Tablets, Compared to Posaconazole Suspension, Does Not Reduce Variability of Posaconazole Trough Concentrations

摘要

The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (C-min) than the oral suspension (POS-susp), which raises the question of the utility of therapeutic drug monitoring (TDM). We aimed to compare the variability of the POS C-min for the two formulations and identify determinants of the POS-tab C-min and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 C-min) treated with POS-tab (n = 41), POS-susp (n = 29), or both (n = 7) from January 2015 to December 2016 were collected retrospectively. Interpatient and within-subject coefficients of variation (CVs) of the C-min adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS C-min was higher for the tablet than for the suspension (median [25th-75th percentile]: 1.8 [1.2-2.4] mg/liter versus 1.2 [0.7-1.6] mg/liter, P < 0.0001). Interpatient CVs for the tablet and suspension were 60.8 versus 63.5% (P = 0.7), whereas within-subject CVs were 39.7 and 44.9%, respectively (P = 0.3). Univariate analysis showed that age and treatment by POS-tab were significantly and positively associated with the POS C-min, whereas diarrhea was associated with a diminished POS C-min. Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS C-min, with a trend toward a lower impact of diarrhea during treatment with POS-tab (P = 0.07). Despite increased POS exposure with the tablet formulation, the variability of the POS C-min was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.