Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study

Background: Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis Cmin target (0.7mg/L) but not of the treatment Cmin target (1.0mg/L). Objectives: To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU. Methods: A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment Cmin and AUC0-24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5. Results: Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300mg q12h and 300mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100kg and ≥100kg, respectively. A maintenance regimen of 400mg q24h ensured ≥90% Cmin PTA, whereas the standard 300mg q24h was sufficient to achieve the AUC0-24 target throughout 14days, irrespective of bodyweight. Conclusions: We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis.