Population pharmacokinetics of posaconazole tablets and Monte-Carlo simulations: should all the patients receive the same dose? [PublishAheadOfPrint]

Background

Posaconazole is extensively used for invasive fungal infection prophylaxis. The gastro-resistant tablet formulation has allowed overcoming bioavailability issues encountered with the oral suspension. However, now overexposure is frequent. This study aimed at (i) describing posaconazole tablets pharmacokinetics in a real-life cohort of patients with haematological malignancies, and (ii) performing Monte-Carlo simulations to assess the possibility to reduce the daily dose while keeping sufficient exposure.

Patients and methods

Forty-nine consecutive inpatients were prospectively included. Posaconazole trough concentrations (TC) were measured once a week and biological and demographic data were collected. Concentrations were analysed by compartment modelling, and Monte-Carlo simulations were performed using estimated parameters to assess the rate of attainment of target TC after dose reduction.

Results

Posaconazole pharmacokinetics was well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were: absorption constant k_a=0.588h^-1 (fixed), distribution volume V/F=420L (28.2%), clearance CL/F=7.3L/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady-state ≥1.5μg/mL and maintained TC above 1μg/mL after dose reduction to 200mg daily. A third of these patients eligible to dose reduction had TC ≥1.5μg/mL as soon as 48h of treatment.

Conclusion

Though less impacted by bioavailability issues than the oral suspension, posaconazole tablets pharmacokinetics remains highly variable. Simulations showed that approximately half of the patients would beneficiate from a dose reduction from 300mg to 200mg while keeping TC above the minimal recommended target of 0.7μg/mL, resulting in a 33% cost saving of this very expensive drug.

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