Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus

The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are bioreleva...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2019-01, Vol.108 (1), p.305-315
Main Authors: Hens, Bart, Bolger, Michael B.
Format: Article
Language:English
Subjects:
absorption
Administration, Oral
clinical pharmacokinetics
Computer Simulation
Drug Compounding
Fasting
Gastrointestinal Absorption - physiology
Gastrointestinal Tract - metabolism
GastroPlus modeling
Humans
Hydrogen-Ion Concentration
in silico modeling
Injections, Intravenous
Models, Biological
pharmacokinetics
pharmacometrics
poorly water-soluble drug
precipitation
simulations
Solubility
Solutions
supersaturation
Triazoles - administration & dosage
Triazoles - blood
Triazoles - chemistry
Triazoles - pharmacokinetics
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Summary:The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus™ to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma Cmax). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2018.10.041