2019 - Stockholm - Sweden

PAGE 2019: Drug/Disease modelling - Infection
Lu Chen

Bioavailability and the Variability of Posaconazole Exposure in Healthy Volunteers Using a Population Pharmacokinetic Analysis

Lu Chen(1), Roger J. BrŘggemann(2), Catherijne A.J. Knibbe(1,3) , Elke H.J. Krekels(1)

(1) Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre of Drug Research, Leiden University, The Netherlands; (2) Department of Pharmacy, Radboud University Medical Centre, Radboud University, The Netherlands; (3) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands

Objectives: Posaconazole is a broad-spectrum, systemic triazole antifungal drug and is widely used for prophylaxis and treatment of invasive fungal disease [1]. Exposure upon administration of the first released formulation, posaconazole suspension, showed high inter-individual pharmacokinetic variability due to erratic absorption [2,3], which can lead to an insufficient exposure and treatment failure. Intravenous posaconazole was subsequently released in response to the potential limitation of the oral suspension [4]. This allows us to establish the oral bioavailability. Our aim is to determine for the first time the absolute oral bioavailability of posaconazole suspension and quantify inter-individual variability of posaconazole pharmacokinetics in healthy volunteers.

Methods: Two healthy volunteer studies were conducted at Radboud university medical center, our analysis included 220 measurements from 20 subjects receiving posaconazole suspension at steady state [5], and 80 measurements from 8 subjects after a single dose of intravenous posaconazole 300 mg. In the intravenous posaconazole dataset, blood samples were collected throughout a 48 h period at 11 pre-defined time points (0.75, 1, 1.25, 1.5, 2, 4, 8, 12, 24, 48 h) after dosing.

NONMEM 7.3 was used to characterize the pharmacokinetics of posaconazole suspension and injection in a healthy adult population. The first-order conditional estimation method with interaction was used during model development. One, two and three compartment models with linear elimination were investigated. First-order absorption (with and without absorption lag time) and a multiple dose transit compartment models were investigated to describe the absorption of posaconazole suspension. For the estimation of bioavailability, a logit transformation was applied to ensure the estimate remained between 0 and 1. Inter-individual variability terms were tested on all pharmacokinetic parameters using log-normal distributions, with the exception of inter-individual variability in bioavailability, which was modeled with a normal distribution in the logit domain. Proportional, additive, and combined additive and proportional residual error models were evaluated. Two covariates, age and weight were investigated on clearance, volume of central and peripheral compartment, which were tested using linear and exponential relationships.

Visual predictive checks based on 1000 simulations were performed for model validation and a bootstrap procedure based on 1000 resampled datasets was used to further test the robustness of the final model.

Results: A two-compartment model with a lag time followed by first-order absorption and a first-order elimination best described the pharmacokinetic profiles of oral and iv posaconazole. The absolute bioavailability of posaconazole suspension was estimated to be 46.3% (residual standard error [RSE], 11.8%). The clearance was 5.9 L/h (RSE, 9.6%) and the lag time was 1.8 h (RSE, 3.3%).

The inter-individual variability for clearance, central volume and peripheral volume were 37.7% (RSE, 11.9%), 29.6% (RSE, 17%) and 101.0% (RSE, 35.9%), respectively. Inter-individual variability on bioavailability could not be identified. A proportional residual error model was used and the goodness-of-fit plots indicated an acceptable model fit. None of the tested covariates was statistically significant in our analysis. The visual predictive checks indicated a good predictive performance, with acceptable agreement between the observations and model-simulated confidence intervals for the 5th, 50th, and 95th percentiles. Parameter estimates from bootstrap were close to those obtained from the original data set, suggests the parameter estimation in the final model is accurate and the model is with no misspecification.

Conclusions: This analysis is the first to quantify absolute bioavailability of the posaconazole suspension as 46.3%, which is slightly lower than the 54% reported for a delayed-release tablet [6]. The investigation of the bioavailability of the posaconazole suspension in various patient populations is part of further investigation.



References:
[1]    Patterson T. F., et al. Clin Infect Dis, 2016, 63 (4): e1-e60.
[2]    Courtney R., et al. Br J Clin Pharmacol, 2004, 57 (2): 218-222.
[3]    Krishna G., et al.. Antimicrob Agents Chemother, 2009, 53 (3): 958-966.
[4]    Kersemaekers W. M., et al. Antimicrob Agents Chemother, 2015, 59 (2): 1246-1251.
[5]    Bruggemann R. J., et al. J Antimicrob Chemother, 2010, 65 (10): 2188-2194.
[6]    Agency European Medicines. https://www.ema.europa.eu/documents/variation-report/noxafil-h-c-610-x-0028-epar-scientific-discussion-extension_en.pdf[J]. 2014.




Reference: PAGE 28 (2019) Abstr 8958 [www.page-meeting.org/?abstract=8958]
Poster: Drug/Disease modelling - Infection
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