Applied Concepts in PBPK Modeling: How to Extend an Open Systems Pharmacology Model to the Special Population of Pregnant Women

Abstract

This tutorial presents the workflow of adapting an adult physiologically based pharmacokinetic (PBPK) model to the pregnant populations using the Open Systems Pharmacology (OSP) software suite (http://www.open-systems-pharmacology.org). This workflow is illustrated using a previously published PBPK model for metronidazole that is extrapolated to pregnancy by parameterizing and extending the model structure in terms of pregnancy‐induced physiological changes. Importantly, this workflow can be applied to other scenarios where PBPK models need to be re‐parameterized or structurally modified.

Development of a Multifunctional Bioerodible Nanocomposite Containing Metronidazole and Curcumin to Apply on L-PRF Clot to Promote Tissue Regeneration in Dentistry

“…Since the aim of the work was to obtain a bifunctional nanocomposite also loaded with the antibacterial agent MTR, its physicochemical characteristics needed to be considered. MTR shows high solubility in water (10.61 mg/mL), particularly at a low pH, having pKa (basic) of 2.49 and LogP = −0.02 [ 51 , 52 ].…”

Physiologically Based Pharmacokinetic Modeling to Characterize Acetaminophen Pharmacokinetics and N-Acetyl-p-Benzoquinone Imine (NAPQI) Formation in Non-Pregnant and Pregnant Women

“…The workflow for constructing and translating a PBPK model to pregnant women ( Fig. 1) has recently been described [12] and is summarized here, as it is relevant to this analysis. PBPK models for acetaminophen were developed for a nonpregnant population for IV administration and then, keeping distribution-and clearance-related parameters unchanged, for oral administration [13].…”

“…At high doses, however, glutathione becomes depleted and NAPQI binds Carlo algorithm implemented in the software's Parameter Identification toolbox. Thereafter, all drug-specific parameters, except the fraction unbound (f u ), were fixed and the model was extrapolated to pregnant women by substituting the standard model structure with the pregnancy model structure, which includes nine additional compartments [2,12]. Pharmacokinetic predictions were performed in a population of pregnant women that matched anthropometric measures of the in vivo study group of pregnant women.…”

Physiologically Based Pharmacokinetic Modeling in Pregnancy: A Systematic Review of Published Models

“…Dallmann et al . recently provided a detailed how‐to tutorial . Figure a depicts the mean plasma concentration–time profile of midazolam in the nonpregnant women as simulated by the three models.…”

“…Dallmann et al recently provided a detailed how-to tutorial. 56 Figure 4a depicts the mean plasma concentration-time profile of midazolam in the nonpregnant women as simulated by the three models. This figure shows that the simulated concentration profiles of all three models were in good agreement with the observed plasma concentration data.…”