Population Pharmacokinetics of Posaconazole Tablets and Monte Carlo Simulations To Determine whether All Patients Should Receive the Same Dose

Abstract

Posaconazole is extensively used for prophylaxis for invasive fungal infections. The gastro-resistant tablet formulation has allowed the bioavailability issues encountered with the oral suspension to be overcome. However, overexposure is now frequent. This study aimed to (i) describe the pharmacokinetics of posaconazole tablets in a real-life cohort of patients with hematological malignancies and (ii) perform Monte Carlo simulations to assess the possibility that the daily dose can be reduced while keeping a sufficient exposure. Forty-nine consecutive inpatients were prospectively included in the study. Posaconazole trough concentrations (TC) were measured once a week, and biological and demographic data were collected. The concentrations were analyzed by compartmental modeling, and Monte Carlo simulations were performed using estimated parameters to assess the rate of attainment of the target TC after dose reduction. The pharmacokinetics of posaconazole were well described using a one-compartment model with first-order absorption and elimination. The values of the parameters (interindividual variabilities) were as follows: the absorption constant ( ) was 0.588 h (fixed), the volume of distribution (/) was 420 liters (28.2%), and clearance (CL/) was 7.3 liters/h (24.2%) with 31.9% interoccasion variability. Forty-nine percent of the simulated patients had TC at steady state of ≥1.5 μg/ml and maintained a TC above 1 μg/ml after a reduction of the dose to 200 mg daily. A third of these patients eligible for a dose reduction had TC of ≥1.5 μg/ml as soon as 48 h of treatment. Though posaconazole tablets were less impacted by bioavailability issues than the oral suspension, the pharmacokinetics of posaconazole tablets remain highly variable. Simulations showed that approximately half of the patients would benefit from a reduction of the dose from 300 mg to 200 mg while keeping the TC above the minimal recommended target of 0.7 μg/ml, resulting in a 33% savings in the cost of this very expensive drug.

Clinical Pharmacokinetics and Dose Recommendations for Posaconazole in Infants and Children

“…2). This was consistent with previous adult models [15,19,20]. Our estimated CL/ F and apparent volume related to the tablet formulation and standardised to a 70-kg individual were 14.95 L/h and b dose estimated dose in mg/m 2 for suspension bioavailability to drop to half that of the tablet, CI confidence interval, CL/F apparent clearance, CV coefficient of variation, Ka absorption rate constant, h D fractional decrease in suspension bioavailability with patients with diarrhea, h P fractional decrease in suspension bioavailability with patients taking proton pump inhibitors, RSE relative standard error, V/F apparent volume 201.68 L, respectively.…”

“…Our estimated CL/ F and apparent volume related to the tablet formulation and standardised to a 70-kg individual were 14.95 L/h and b dose estimated dose in mg/m 2 for suspension bioavailability to drop to half that of the tablet, CI confidence interval, CL/F apparent clearance, CV coefficient of variation, Ka absorption rate constant, h D fractional decrease in suspension bioavailability with patients with diarrhea, h P fractional decrease in suspension bioavailability with patients taking proton pump inhibitors, RSE relative standard error, V/F apparent volume 201.68 L, respectively. In a recent study of adults, CL/F and apparent volume were estimated to be 7.3 L/h and 420 L, respectively [19], which fall within the 95% confidence intervals of our estimates (Table 2). Fixing the absorption rate to that previously reported in adults had a negligible effect on model fit, and the flat profiles, the fact our data did not include any patients sampled after their first dose, and the limited number of samples in the absorption phase all account for this.…”

“…Thereafter, Ka was fixed to literature values of 0.588/h for tablets [19], and 0.197/h for suspensions [15]. The difference in OFV between this model and the estimated Ka and V models was 7.63, indicating a very similar fit.…”

<p>Pharmacokinetic/pharmacodynamic study of posaconazole delayed-release tablet in a patient with coexisting invasive aspergillosis and mucormycosis</p>

“…and Mucorales that had high MICs in our patient. This finding is consistent with a previous population pharmacokinetic study that found that approximately 72.6% of patients achieved the posaconazole minimum concentration target after 48 hrs of treatment 20. This may be due to the inter-individual variability and inter-occasion variability pharmacokinetic characteristics of posaconazole 20.…”

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

“…This greater POS C min could theoretically result in a greater risk of side effects, although no study has yet clearly highlighted increased toxicity with the POS tablet formulation [2,[9][10][11][12][13][14]. Hence, no upper threshold for the POS C min has yet been proposed, even if some authors have suggested that dose reduction could be feasible for at least half of patients [15,16]. It is therefore necessary to precise the upper limit of POS C min above which POS dosing could be reduced.…”