Lu Chen (1), Elke H.J. Krekels (1), Catherijne A.J. Knibbe (1,2), Roger J.M. Brüggemann (3,4)
(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands, (2) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands, (3) Department of Pharmacy, Radboud University Medical Centre, Radboud University, Nijmegen, The Netherlands, (4) Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands
Objectives: Posaconazole is widely used for prophylaxis and treatment of invasive fungal diseases. Due to limited and variable absorption for the oral suspension, a delayed-released tablet (DR-tablet) was developed, followed by an iv formulation. As no study has compared the pharmacokinetics of all formulations simultaneously, we here use a population pharmacokinetic modeling approach to quantify the pharmacokinetics of all formulations, including the absolute oral bioavailability (F) of the two oral formulations and the impact of food intake and comedication on absorption in healthy volunteers. Model-based simulations were used to illustrate our findings.
Methods: Data from 182 healthy volunteers with 3898 densely sampled posaconazole concentrations were pooled from 8 phase I clinical studies on three formulations of various dosages between 50 and 400 mg [1-8]. Population pharmacokinetic analysis and simulations were performed using NONMEM 7.5.0 supported by Perl-speaks-NONMEM (v5.2.6) with the Pirana interface (v3.0.0, Certara USA, Inc, Princeton, USA). Data pre-processing and visualization were performed with R 4.0.3 and RStudio 1.3.959. One-, two-, and three-compartment disposition models were tested. Logit transformation was applied on the F and the corresponding interindividual variability was incorporated in the logit domain. Tested approaches to describe oral absorption included first-order absorption (with and without absorption lag time), transit compartment models[9,10], mixed first-order and zero-order absorption[11,12], and a Weibull function[12]. Nonlinearity on F and clearance (CL) were tested to investigate saturation in the absorption and elimination of posaconazole. For the covariate analysis, the influence of fed or fasted conditions was available for suspension and DR-tablet, and comedication (antacid, ranitidine, esomeprazole, and metoclopramide) for the DR-tablet only. A total of 7.7% concentrations were below the quantification limit (BQL). Due to the long run times, the M1 method was applied to deal with BQL concentrations during model development, after confirmation that the estimation results were similar between the M1 and M3 methods for the base model. The M3 method was used for the fit of the final model. The first-order conditional estimation method with interaction, LAPLACIAN in combination with the stochastic approximation expectation-maximization method was used for models using M1 and M3 methods to accommodate BQL data, respectively.
Results: A two-compartment disposition model was adopted for all formulations and respectively four and seven absorption transit compartments best described the absorption profiles for the suspension and DR-tablet. Within the available dose range, nonlinearity could not be identified with statistical significance on F nor on CL. The F of the suspension and DR-tablet was 18.8% (95% confidence interval [CI] 15.1-22.5%) versus 58.2% (CI 53.2-63.2%) under fasted conditions. The F of the suspension was increased by 3.12-fold (CI 2.45-3.79) under fed conditions, with the F of the DR-tablet being fixed to 99.5% due to boundary problems. Food intake was also found to reduce the absorption rate constant of the suspension by 53.5% (CI 46.2-60.9%). The impact of comedication on the absorption of the DR-tablet was not statistically significant. Simulation results indicated that typical healthy volunteers receiving common dosages of three formulations yield concentrations above a previously reported prophylactic trough concentration of 0.7 mg/L[13], except for the suspension of 200 mg three times daily under fasted conditions.
Conclusions: In this study, we are the first to quantify the F and oral absorption including the influence of food for both oral formulations against intravenous administration in healthy volunteers in one analysis. The pharmacokinetic superiority of the DR-tablet was demonstrated under both fasted and fed conditions compared with the oral suspension. The impact of food on the F of the DR-tablet was larger than anticipated, which suggests that administering the DR-tablet with food should be considered to enhance absorption. Future investigation focusing on the pharmacokinetic difference between healthy individuals and patients in three formulations is warranted.
References:
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Reference: PAGE 30 (2022) Abstr 10036 [www.page-meeting.org/?abstract=10036]
Poster: Drug/Disease Modelling - Infection