A population pharmacokinetic model for posaconazole intravenous solution and oral powder for suspension formulations in pediatric patients with neutropenia

Abstract

The objective of this study was to support posaconazole dose regimens in pediatric patients aged ≥2 years, using a population pharmacokinetic (PK) approach with data from a phase 1b study (NCT02452034). A one-compartment model with first-order absorption was fit to pharmacokinetic data from 144 participants aged 2 to 17 years, who were administered posaconazole as intravenous (IV) and powder for oral suspension (PFS) formulations, or IV only, at dosing regimens of 3.5, 4.5, and 6 mg/kg. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final model simulated posaconazole exposure in patients aged 2 to <7 and 7 to 17 years at dosing regimens of 4.5, 6, and 7.5 mg/kg. Plasma concentration data following IV and PFS administration were well-described by a one-compartment model with first-order absorption and estimated bioavailability, where clearance and volume were subject to allometric scaling by body weight. The 6-mg/kg dosing regimen achieved the pharmacokinetic target (90% of the pediatric population having an average steady-state plasma concentration of ≥500 and <2,000 ng/mL) for both age groups, regardless of whether patients received IV and PFS or IV only. In a virtual adolescent population (body weight >40 kg), the 300 mg/day posaconazole tablet was also predicted to achieve the pharmacokinetic target and remain within a safe range of exposure. These data informed a weight-based nomogram for PFS dosing to maximize the number of pediatric patients achieving the pharmacokinetic target across weight bands, while also maintaining a favorable benefit/risk profile.

Keywords: antifungal agents; invasive fungal disease; pediatrics; pharmacokinetics; posaconazole.

Fig 1

Correlation of interindividual variability with the relative bioavailability of the posaconazole PFS formulation vs two-category food effect covariates. Graphical assessments of the IIV of the posaconazole PFS formulation for (a) the overall food effect parameter, (b) food intake within 2 hours before dosing, and (c) food intake within 1 hour post-dose. N represents the number of observations with certain associated food information. The line in the box represents median, boxes extend to the 25th and 75th percentiles, and whiskers extend to the 5th and 95th percentiles. F1, relative bioavailability; IIV, interindividual variability; PFS, powder for oral suspension; POS, posaconazole.

Fig 2

Goodness-of-fit analysis for the final structural pharmacokinetic model. Goodness-of-fit plots for (a) log of observed posaconazole concentrations (ng/mL) vs the log of individual predicted posaconazole concentrations (ng/mL), (b) log of observed posaconazole concentrations (ng/mL) vs the log of population predicted posaconazole concentrations (ng/mL), (c) frequency of individual conditional weighted residuals, and (d) conditional weight residuals vs the log of population-predicted posaconazole concentrations (ng/mL). Excludes outlier observations. In (a), (b), and (d), dots represent individual data and solid gray lines represent trend lines. In (a) and (b), the black dashed lines are lines of identity. In (d), the black dashed line represents a reference (zero) line.

Fig 3

Distribution of simulated C_avg per age group and formulation. Distribution of simulated posaconazole C_avg per age group (2 to <7 or 7 to 17 years) and formulation (IV or PFS) at (a) 4.5, (b) 6, (c) and 7.5 mg/kg. The vertical dashed line is the geometric mean of the pharmacokinetic parameter. The left and right solid lines represent the thresholds of 500 and 2,500 ng/mL, respectively. C_avg, average steady-state plasma concentration; IV, intravenous; PFS, powder for oral suspension.

Fig 4

Distribution of model-predicted C_avg by body weight for posaconazole tablets and PFS in virtual pediatric subjects and observed distribution of C_avg for posaconazole tablets in adults. Frequency distribution of model-predicted C_avg by body weight for the 300 mg QD posaconazole tablet and the 6-mg/kg QD PFS dosing schedule in virtual pediatric patients vs the distribution of C_avg for the 300 mg QD posaconazole tablet observed in adults from a previous study (14), across 28 days of dosing. The line in the box represents the median, boxes extend to the 25th and 75th percentiles, and whiskers extend to the 5th and 95th percentiles. The dashed line represents the 500 ng/mL posaconazole C_avg target concentration. C_avg, average steady-state plasma concentration; IV, intravenous; PFS, powder for oral suspension; QD, once daily.