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Pharmaceutics Jun 2024The philosophy, practice, and clinical impact of therapeutic drug monitoring (TDM) has changed profoundly with the appearance of widely available and, in a technical...
The philosophy, practice, and clinical impact of therapeutic drug monitoring (TDM) has changed profoundly with the appearance of widely available and, in a technical sense, commonly applicable modeling, simulation, and dosing software tools in the past decade [...].
PubMed: 38931913
DOI: 10.3390/pharmaceutics16060792 -
Pharmaceutics Jun 2024Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption,...
Understanding the pharmacokinetics, safety and efficacy of candidate drugs is crucial for their success. One key aspect is the characterization of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties, which require early assessment in the drug discovery and development process. This study aims to present an innovative approach for predicting ADMET properties using attention-based graph neural networks (GNNs). The model utilizes a graph-based representation of molecules directly derived from Simplified Molecular Input Line Entry System (SMILE) notation. Information is processed sequentially, from substructures to the whole molecule, employing a bottom-up approach. The developed GNN is tested and compared with existing approaches using six benchmark datasets and by encompassing regression (lipophilicity and aqueous solubility) and classification (CYP2C9, CYP2C19, CYP2D6 and CYP3A4 inhibition) tasks. Results show the effectiveness of our model, which bypasses the computationally expensive retrieval and selection of molecular descriptors. This approach provides a valuable tool for high-throughput screening, facilitating early assessment of ADMET properties and enhancing the likelihood of drug success in the development pipeline.
PubMed: 38931898
DOI: 10.3390/pharmaceutics16060776 -
Pharmaceutics Jun 2024Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended,...
BACKGROUND
Unfractionated heparin is administered in patients undergoing veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Anticoagulation monitoring is recommended, with an anti-activated factor X (anti-Xa) targeting 0.3 to 0.7 IU/mL. Owing to heparin's heterogeneous pharmacokinetic properties, anti-Xa is unpredictable, generating a challenge in anticoagulation practices. The aim of this study was to build a pharmacokinetic model of heparin accounting for potential confounders, and derive an optimized dosing regimen for a given anti-Xa target.
METHODS
Adult patients undergoing VA-ECMO were included between January 2020 and June 2021. Anticoagulation was managed with an initial 100 IU/kg heparin loading dose followed by a continuous infusion targeting 0.2 to 0.7 IU/mL anti-Xa. The data were split into model development and model validation cohorts. Statistical analysis was performed using a nonlinear mixed effects modeling population approach. Model-based simulations were performed to develop an optimized dosing regimen targeting the desired anti-Xa.
RESULTS
A total of 74 patients were included, with 1703 anti-Xa observations. A single-compartment model best fitted the data. Interpatient variability for distribution volume was best explained by body weight, C-reactive protein and ECMO indication (post-cardiotomy shock or medical cardiogenic shock), and interpatient variability for elimination clearance was best explained by serum creatinine and C-reactive protein. Simulations using the optimized regimen according to these covariates showed accurate anti-Xa target attainment.
CONCLUSION
In adult patients on VA-ECMO, heparin's effect increased with serum creatinine and medical indication, whereas it decreased with body weight and systemic inflammation. We propose an optimized dosing regimen accounting for key covariates, capable of accurately predicting a given anti-Xa target.
PubMed: 38931891
DOI: 10.3390/pharmaceutics16060770 -
Pharmaceutics Jun 2024Drug absorption via chylomicrons holds significant implications for both pharmacokinetics and pharmacodynamics. However, a mechanistic understanding of predicting in...
Drug absorption via chylomicrons holds significant implications for both pharmacokinetics and pharmacodynamics. However, a mechanistic understanding of predicting in vivo intestinal lymphatic uptake remains largely unexplored. This study aimed to delve into the intestinal lymphatic uptake of drugs, investigating both enhancement and inhibition using various excipients through our previously established in vitro model. It also examined the applicability of the model by assessing the lymphatic uptake enhancement of a lymphotropic formulation with linoleoyl polyoxyl-6 glycerides using the same model. The model successfully differentiated among olive, sesame, and peanut oils in terms of lymphatic uptake. However, it did not distinguish between oils containing long-chain fatty acids and coconut oil. Coconut oil, known for its abundance of medium-chain fatty acids, outperformed other oils. This heightened uptake was attributed to the superior emulsification of this oil in artificial chylomicron media due to its high content of medium-chain fatty acids. Additionally, the enhanced uptake of the tested formulation with linoleoyl polyoxyl-6 glycerides underscored the practical applicability of this model in formulation optimization. Moreover, data suggested that increasing the zeta potential of Intralipid using sodium lauryl sulfate (SLS) and decreasing it using (+/-) chloroquine led to enhanced and reduced uptake in the in vitro model, respectively. These findings indicate the potential influence of the zeta potential on intestinal lymphatic uptake in this model, though further research is needed to explore the possible translation of this mechanism in vivo.
PubMed: 38931889
DOI: 10.3390/pharmaceutics16060768 -
Pharmaceutics Jun 2024Natural compounds such as polyphenols play several positive roles in maintaining the oxidative and inflammatory capacity of cells, which leads to their potential use as... (Review)
Review
Natural compounds such as polyphenols play several positive roles in maintaining the oxidative and inflammatory capacity of cells, which leads to their potential use as anticancer therapeutics. There is promising evidence for the in vitro and in vivo anticancer activity of many polyphenols, including resveratrol and quercetin, specifically in the treatment of colorectal cancer (CRC). There is a clear association between resveratrol and quercetin in interfering with the mechanistic pathways involved in CRC, such as Wnt, P13K/AKT, caspase-3, MAPK, NF-κB, etc. These molecular pathways establish the role of resveratrol and quercetin in controlling cancer cell growth, inducing apoptosis, and inhibiting metastasis. The major bottleneck in the progression of the use of resveratrol and quercetin as anticancer therapeutics is their reduced bioavailability in vivo because of their rapid metabolism in humans. Recent advancements in various nanotechnological formulations are promising for overcoming these bioavailability issues. Various nanoformulations of resveratrol and quercetin have shown an optimistic impact on reducing the solubility and improving the stability of resveratrol and quercetin in vivo. A combinatorial approach using nanoformulations of resveratrol with quercetin could potentially increase the impact of resveratrol in controlling CRC cell proliferation. This review discusses the mechanism of resveratrol and quercetin, the two bioactive polyphenolics, in colon cancer, with an emphasis on various types of nanoformulations of the two molecules targeting colon cancer. It also explores the synergistic effect of combining resveratrol and quercetin in various nanoformulations, targeting colon cancer. This research delves into the enhanced pharmacokinetics and potential chemotherapeutic benefits of these bioactive polyphenolics when used together in innovative ways.
PubMed: 38931884
DOI: 10.3390/pharmaceutics16060761 -
Pharmaceutics May 2024Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of...
Applying Physiologically Based Pharmacokinetic Modeling to Interpret Carbamazepine's Nonlinear Pharmacokinetics and Its Induction Potential on Cytochrome P450 3A4 and Cytochrome P450 2C9 Enzymes.
Carbamazepine (CBZ) is commonly prescribed for epilepsy and frequently used in polypharmacy. However, concerns arise regarding its ability to induce the metabolism of other drugs, including itself, potentially leading to the undertreatment of co-administered drugs. Additionally, CBZ exhibits nonlinear pharmacokinetics (PK), but the root causes have not been fully studied. This study aims to investigate the mechanisms behind CBZ's nonlinear PK and its induction potential on CYP3A4 and CYP2C9 enzymes. To achieve this, we developed and validated a physiologically based pharmacokinetic (PBPK) parent-metabolite model of CBZ and its active metabolite Carbamazepine-10,11-epoxide in GastroPlus. The model was utilized for Drug-Drug Interaction (DDI) prediction with CYP3A4 and CYP2C9 victim drugs and to further explore the underlying mechanisms behind CBZ's nonlinear PK. The model accurately recapitulated CBZ plasma PK. Good DDI performance was demonstrated by the prediction of CBZ DDIs with quinidine, dolutegravir, phenytoin, and tolbutamide; however, with midazolam, the predicted/observed DDI AUC ratio was 0.49 (slightly outside of the two-fold range). CBZ's nonlinear PK can be attributed to its nonlinear metabolism caused by autoinduction, as well as nonlinear absorption due to poor solubility. In further applications, the model can help understand DDI potential when CBZ serves as a CYP3A4 and CYP2C9 inducer.
PubMed: 38931859
DOI: 10.3390/pharmaceutics16060737 -
Pharmaceutics May 2024Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can...
Pharmaceutical excipient PEG400 is a common component of traditional Chinese medicine compound preparations. Studies have demonstrated that pharmaceutical excipients can directly or indirectly influence the disposition process of active drugs in vivo, thereby affecting the bioavailability of drugs. In order to reveal the pharmacokinetic effect of PEG400 on baicalin in hepatocytes and its mechanism, the present study first started with the effect of PEG400 on the metabolic disposition of baicalin at the hepatocyte level, and then the effect of PEG400 on the protein expression of baicalin-related transporters (BCRP, MRP2, and MRP3) was investigated by using western blot; the effect of MDCKII-BCRP, MDCKII-BCRP, MRP2, and MRP3 was investigated by using MDCKII-BCRP, MDCKII-MRP2, and MDCKII-MRP3 cell monolayer models, and membrane vesicles overexpressing specific transporter proteins (BCRP, MRP2, and MRP3), combined with the exocytosis of transporter-specific inhibitors, were used to study the effects of PEG400 on the transporters in order to explore the possible mechanisms of its action. The results demonstrated that PEG400 significantly influenced the concentration of baicalin in hepatocytes, and the AUC of baicalin increased from 75.96 ± 2.57 μg·h/mL to 106.94 ± 2.22 μg·h/mL, 111.97 ± 3.98 μg·h/mL, and 130.42 ± 5.26 μg·h/mL ( ˂ 0.05). Furthermore, the efflux rate of baicalin was significantly reduced in the vesicular transport assay and the MDCKII cell model transport assay, which indicated that PEG400 had a significant inhibitory effect on the corresponding transporters. In conclusion, PEG400 can improve the bioavailability of baicalin to some extent by affecting the efflux transporters and thus the metabolic disposition of baicalin in the liver.
PubMed: 38931853
DOI: 10.3390/pharmaceutics16060731 -
Pharmaceutics May 2024The compound 6-methoxyseselin, derived from , demonstrates various therapeutic properties, including vasorelaxation, antinociceptive, anti-inflammatory, and...
The compound 6-methoxyseselin, derived from , demonstrates various therapeutic properties, including vasorelaxation, antinociceptive, anti-inflammatory, and immunomodulatory effects, along with recently discovered antiasthmatic properties. This study aimed to evaluate its preclinical pharmacokinetics and pulmonary delivery in Balb/c mice. The method involved administering the compound via inhalation and intravenous routes, followed by blood sample collection for analysis using high-performance liquid chromatography with diode array detection (HPLC-DAD). The results indicated good linearity, precision, accuracy, and stability of the compound in the biological samples. Pharmacokinetic parameters such as the rate of elimination, half-life, clearance, volume of distribution, area under the curve, and mean residence time were determined for both administration routes, showing similar profiles. The lung concentrations were notably higher than the plasma concentrations, indicating significant lung penetration. These findings suggest 6-methoxyseselin as a promising candidate for new anti-asthmatic drugs, supported by its favorable pharmacokinetic profiles and high lung penetration factors. This study represents the first exploration of the pharmacokinetics and pulmonary delivery of 6-methoxyseselin in mice, highlighting its potential for further drug development.
PubMed: 38931838
DOI: 10.3390/pharmaceutics16060714 -
Pharmaceutics May 2024Paediatric infectious diseases contribute significantly to global health challenges. Conventional therapeutic interventions are not always suitable for children, as they... (Review)
Review
Paediatric infectious diseases contribute significantly to global health challenges. Conventional therapeutic interventions are not always suitable for children, as they are regularly accompanied with long-standing disadvantages that negatively impact efficacy, thus necessitating the need for effective and child-friendly pharmacotherapeutic interventions. Recent advancements in drug delivery technologies, particularly oral formulations, have shown tremendous progress in enhancing the effectiveness of paediatric medicines. Generally, these delivery methods target, and address challenges associated with palatability, dosing accuracy, stability, bioavailability, patient compliance, and caregiver convenience, which are important factors that can influence successful treatment outcomes in children. Some of the emerging trends include moving away from creating liquid delivery systems to developing oral solid formulations, with the most explored being orodispersible tablets, multiparticulate dosage forms using film-coating technologies, and chewable drug products. Other ongoing innovations include gastro-retentive, 3D-printed, nipple-shield, milk-based, and nanoparticulate (e.g., lipid-, polymeric-based templates) drug delivery systems, possessing the potential to improve therapeutic effectiveness, age appropriateness, pharmacokinetics, and safety profiles as they relate to the paediatric population. This manuscript therefore highlights the evolving landscape of oral pharmacotherapeutic interventions for leading paediatric infectious diseases, crediting the role of innovative drug delivery technologies. By focusing on the current trends, pointing out gaps, and identifying future possibilities, this review aims to contribute towards ongoing efforts directed at improving paediatric health outcomes associated with the management of these infectious ailments through accessible and efficacious drug treatments.
PubMed: 38931836
DOI: 10.3390/pharmaceutics16060712 -
Pharmaceutics May 2024Most traditional cytotoxic drugs are characterized by steep dose-response relationships and narrow therapeutic windows [...].
Most traditional cytotoxic drugs are characterized by steep dose-response relationships and narrow therapeutic windows [...].
PubMed: 38931835
DOI: 10.3390/pharmaceutics16060711