Mechanistic Modeling of In Vitro Biopharmaceutic Data for a Weak Acid Drug: A Pathway Towards Deriving Fundamental Parameters for Physiologically Based Biopharmaceutic Modeling.

Mechanistic modeling of in vitro experiments using metabolic enzyme systems enables the extrapolation of metabolic clearance for in vitro-in vivo predictions. This is particularly important for successful clearance predictions using physiologically based pharmacokinetic (PBPK) modeling. The concept of mechanistic modeling can also be extended to biopharmaceutics, where in vitro data is used to predict the in vivo pharmacokinetic profile of the drug. This approach further allows for the identification of parameters that are critical for oral drug absorption in vivo. However, the routine use of this analysis approach has been hindered by the lack of an integrated analysis workflow. The objective of this tutorial is to (1) review processes and parameters contributing to oral drug absorption in increasing levels of complexity, (2) outline a general physiologically based biopharmaceutic modeling workflow for weak acids, and (3) illustrate the outlined concepts via an ibuprofen (i.e., a weak, poorly soluble acid) case example in order to provide practical guidance on how to integrate biopharmaceutic and physiological data to better understand oral drug absorption. In the future, we plan to explore the usefulness of this tutorial/roadmap to inform the development of PBPK models for BCS 2 weak bases, by expanding the stepwise modeling approach to accommodate more intricate scenarios, including the presence of diprotic basic compounds and acidifying agents within the formulation.

Targeting Allosteric Site of PCSK9 Enzyme for the Identification of Small Molecule Inhibitors: An In Silico Drug Repurposing Study.

The primary cause of atherosclerotic cardiovascular disease (ASCVD) is elevated levels of low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in this process by binding to the LDL receptor (LDL-R) domain, leading to reduced influx of LDL-C and decreased LDL-R cell surface presentation on hepatocytes, resulting higher circulating levels of LDL-C. As a consequence, PCSK9 has been identified as a crucial target for drug development against dyslipidemia and hypercholesterolemia, aiming to lower plasma LDL-C levels. This research endeavors to identify promising inhibitory candidates that target the allosteric site of PCSK9 through an in silico approach. To start with, the FDA-approved Drug Library from Selleckchem was selected and virtually screened by docking studies using Glide extra-precision (XP) docking mode and Smina software (Version 1.1.2). Subsequently, rescoring of 100 drug compounds showing good average docking scores were performed using Gnina software (Version 1.0) to generate CNN Score and CNN binding affinity. Among the drug compounds, amikacin, bestatin, and natamycin were found to exhibit higher docking scores and CNN affinities against the PCSK9 enzyme. Molecular dynamics simulations further confirmed that these drug molecules established the stable protein-ligand complexes when compared to the apo structure of PCSK9 and the complex with the co-crystallized ligand structure. Moreover, the MM-GBSA calculations revealed binding free energy values ranging from -84.22 to -76.39 kcal/mol, which were found comparable to those obtained for the co-crystallized ligand structure. In conclusion, these identified drug molecules have the potential to serve as inhibitors PCSK9 enzyme and these finding could pave the way for the development of new PCSK9 inhibitory drugs in future in vitro research.

A network immuno-epidemiological model of HIV and opioid epidemics.

In this paper, we introduce a novel multi-scale network model of two epidemics: HIV infection and opioid addiction. The HIV infection dynamics is modeled on a complex network. We determine the basic reproduction number of HIV infection, $ \mathcal{R}_{v} $, and the basic reproduction number of opioid addiction, $ \mathcal{R}_{u} $. We show that the model has a unique disease-free equilibrium which is locally asymptotically stable when both $ \mathcal{R}_{u} $ and $ \mathcal{R}_{v} $ are less than one. If $ \mathcal{R}_{u} > 1 $ or $ \mathcal{R}_{v} > 1 $, then the disease-free equilibrium is unstable and there exists a unique semi-trivial equilibrium corresponding to each disease. The unique opioid only equilibrium exist when the basic reproduction number of opioid addiction is greater than one and it is locally asymptotically stable when the invasion number of HIV infection, $ \mathcal{R}^{1}_{v_i} $ is less than one. Similarly, the unique HIV only equilibrium exist when the basic reproduction number of HIV is greater than one and it is locally asymptotically stable when the invasion number of opioid addiction, $ \mathcal{R}^{2}_{u_i} $ is less than one. Existence and stability of co-existence equilibria remains an open problem. We performed numerical simulations to better understand the impact of three epidemiologically important parameters that are at the intersection of two epidemics: $ q_v $ the likelihood of an opioid user being infected with HIV, $ q_u $ the likelihood of an HIV-infected individual becoming addicted to opioids, and $ \delta $ recovery from opioid addiction. Simulations suggest that as the recovery from opioid use increases, the prevalence of co-affected individuals, those who are addicted to opioids and are infected with HIV, increase significantly. We demonstrate that the dependence of the co-affected population on $ q_u $ and $ q_v $ are not monotone.

Immuno-epidemiological co-affection model of HIV infection and opioid addiction.

In this paper, we present a multi-scale co-affection model of HIV infection and opioid addiction. The population scale epidemiological model is linked to the within-host model which describes the HIV and opioid dynamics in a co-affected individual. CD4 cells and viral load data obtained from morphine addicted SIV-infected monkeys are used to validate the within-host model. AIDS diagnoses, HIV death and opioid mortality data are used to fit the between-host model. When the rates of viral clearance and morphine uptake are fixed, the within-host model is structurally identifiable. If in addition the morphine saturation and clearance rates are also fixed the model becomes practical identifiable. Analytical results of the multi-scale model suggest that in addition to the disease-addiction-free equilibrium, there is a unique HIV-only and opioid-only equilibrium. Each of the boundary equilibria is stable if the invasion number of the other epidemic is below one. Elasticity analysis suggests that the most sensitive number is the invasion number of opioid epidemic with respect to the parameter of enhancement of HIV infection of opioid-affected individual. We conclude that the most effective control strategy is to prevent opioid addicted individuals from getting HIV, and to treat the opioid addiction directly and independently from HIV.

A Network Immuno-Epidemiological HIV Model.

In this paper we formulate a multi-scale nested immuno-epidemiological model of HIV on complex networks. The system is described by ordinary differential equations coupled with a partial differential equation. First, we prove the existence and uniqueness of the immunological model and then establish the well-posedness of the multi-scale model. We derive an explicit expression of the basic reproduction number [Formula: see text] of the immuno-epidemiological model. The system has a disease-free equilibrium and an endemic equilibrium. The disease-free equilibrium is globally stable when [Formula: see text] and unstable when [Formula: see text]. Numerical simulations suggest that [Formula: see text] increases as the number of nodes in the network increases. Further, we find that for a scale-free network the number of infected individuals at equilibrium is a hump-like function of the within-host reproduction number; however, the dependence becomes monotone if the network has predominantly low connectivity nodes or high connectivity nodes.