Revisiting the in-vitro and in-vivo considerations for in-silico modelling of complex injectable drug products

Dabke, Amit; Ghosh, Saikat; Dabke, Pallavi; Sawant, Krutika; Khopade, Ajay

doi:10.1016/j.jconrel.2023.06.029

Cited by 2 publications

(3 citation statements)

References 215 publications

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“…Second, rectal absorption was focused on the pediatric rectal PBPK model. The cumulative release fraction in vivo was obtained by the numerical deconvolution method and fitted by the Weibull function . The permeability, fluid volume, length, and radius of the rectum were included as pediatric extrapolation factors in the Weibull function.…”

Section: Methodsmentioning

confidence: 99%

“…The cumulative release fraction in vivo was obtained by the numerical deconvolution method and fitted by the Weibull function. 22 The permeability, fluid volume, length, and radius of the rectum were included as pediatric extrapolation factors in the Weibull function. Third, the pediatric sedation levels were transformed and fitted by the logistic regression PD model to predict the probability of sedation at a particular drug exposure.…”

Section: Overall Strategymentioning

confidence: 99%

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Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling

Zhu,

Zhou,

Wang

et al. 2024

Mol. Pharmaceutics

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This study aims to explore and characterize the role of pediatric sedation via rectal route. A pediatric physiologically based pharmacokineticpharmacodynamic (PBPK/PD) model of midazolam gel was built and validated to support dose selection for pediatric clinical trials. Before developing the rectal PBPK model, an intravenous PBPK model was developed to determine drug disposition, specifically by describing the ontogeny model of the metabolic enzyme. Pediatric rectal absorption was developed based on the rectal PBPK model of adults. The improved Weibull function with permeability, surface area, and fluid volume parameters was used to extrapolate pediatric rectal absorption. A logistic regression model was used to characterize the relationship between the free concentrations of midazolam and the probability of sedation. All models successfully described the PK profiles with absolute average fold error (AAFE) < 2, especially our intravenous PBPK model that extended the predicted age to preterm. The simulation results of the PD model showed that when the free concentrations of midazolam ranged from 3.9 to 18.4 ng/mL, the probability of "Sedation" was greater than that of "Not-sedation" states. Combined with the rectal PBPK model, the recommended sedation doses were in the ranges of 0.44−2.08 mg/kg for children aged 2−3 years, 0.35−1.65 mg/kg for children aged 4−7 years, 0.24−1.27 mg/kg for children aged 8−12 years, and 0.20−1.10 mg/kg for adolescents aged 13−18 years. Overall, this model mechanistically quantified drug disposition and effect of midazolam gel in the pediatric population, accurately predicted the observed clinical data, and simulated the drug exposure for sedation that will inform dose selection for following pediatric clinical trials.

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Section: Methodsmentioning

confidence: 99%

Section: Overall Strategymentioning

confidence: 99%

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling

Zhu,

Zhou,

Wang

et al. 2024

Mol. Pharmaceutics

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show abstract

“…In drug development research, the typical stages that need to be traversed include in vitro testing, in vivo testing on test animals, in vivo testing, followed by clinical trials before eventually allowing use in general [27]. These stages come with various limitations such as high costs, lengthy durations, and uncertain success rates [28].…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking Analysis of Flavonoid Compounds from <em>Glycyrrhiza glabra</em> on the Interleukin – 1 Receptor (IL-1R) as a Candidate for Anti-Inflammatory Drug in Periodontitis

Auerkari,

Andriawan,

Auerkari

2023

Preprint

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Periodontitis is a disease that originates from gingival tissue, and if left untreated, can cause inflammation to spread to deeper tissues, altering bone homeostasis, and even leading to tooth loss. When the bacteria in plaque reach sufficient numbers, the immune system responds by activating immune cells that will produce cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These immune signaling molecules will coordinate the inflammatory responses. IL-1 binds to the IL-1 receptor (IL-1R) on the surface of target cells, initiating an inflammatory response by activating intracellular signalling pathways. Inhibition of IL-1R can prevent the interaction of IL-1 with this receptor, thereby halting the activation of the inflammatory pathway. By substituting this connection with active anti-inflammatory substances, it is possible to prevent the contact between IL-1 and IL-1R. The licorice plant, Glycyrrhiza glabra, includes eight types of flavonoids with significant anti-inflammatory potential, namely isoliquiritigenin, glyzaglabrin, prunetin, shinpterocarpin, licochalcone A, glabridin, glisoflavone, and isoangustone A. This study aims to assess the potential of such flavonoids as candidates for periodontitis treatment through molecular docking, using AutoDock Tools v.1.5.6. All tested compounds showed highly stable bonds to IL-1R, with a binding affinity values below -7 kcal/mol. Van der Waals forces, hydrogen bonds, and hydrophobic bonds all contribute to the stability of these interactions. Among the eight tested compounds, glisoflavone, which has a Ki value of 90.89 nM and a ΔG value of -9.61 kcal/mol, has the highest binding stability to IL-1R.

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Revisiting the in-vitro and in-vivo considerations for in-silico modelling of complex injectable drug products

Cited by 2 publications

References 215 publications

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling

Characterization of Pediatric Rectal Absorption, Drug Disposition, and Sedation Level for Midazolam Gel Using Physiologically Based Pharmacokinetic/Pharmacodynamic Modeling

Molecular Docking Analysis of Flavonoid Compounds from <em>Glycyrrhiza glabra</em> on the Interleukin – 1 Receptor (IL-1R) as a Candidate for Anti-Inflammatory Drug in Periodontitis

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