Treatment by posaconazole tablets, compared to posaconazole suspension, does not reduce variability of posaconazole trough concentrations

Abstract

The delayed-release tablet formulation of posaconazole (POS-tab) results in higher plasma POS trough concentrations (Cm in) 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 Cm in for the two formulations and identify determinants of the POS-tab Cm in and its variability. Demographic, biological, and clinical data from 77 allogeneic hematopoietic stem cell transplant patients (874 Cm in) 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 Cm in adjusted to dose (D) were calculated for each formulation. Between-group comparisons were performed using a linear mixed effects model. The POS Cm in 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 Cm in, whereas diarrhea was associated with a diminished POS Cm in. Multivariate analysis identified treatment with POS-tab and diarrhea as independent factors of the POS Cm in, 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 Cm in was not significantly lower than that of the suspension. This suggests that TDM may still be useful to optimize tablet POS therapy.