Pharmacokinetic Research Articles

Discovery of Novel 5-(Pyridazin-3-yl)pyrimidine-2,4(1H,3H)-dione Derivatives as Potent and Orally Bioavailable Inhibitors Targeting Ecto-5'-nucleotidase.

Ecto-5-nucleotidase (CD73) is overexpressed in a variety of cancers and associated with the immunosuppressive tumor microenvironment, making it an attractive target for cancer immunotherapy. Herein, we designed and synthesized a series of novel (pyridazine-3-yl)pyrimidine-2,4(1H,3H)-dione derivatives as CD73 inhibitors. These compounds exhibited remarkable inhibitory activity against CD73 in both enzymatic biochemical and cellular assays. Among them, compound 35j proved to be one of the most potent inhibitors and an uncompetitive inhibitor with no obvious cytotoxicity. This compound showed high metabolic stability in rat liver microsomes and favorable pharmacokinetic profiles in rats (T1/2 = 3.37 h, F = 50.24%). Importantly, orally administered 35j significantly inhibited tumor growth in the triple-negative breast cancer 4T1 mouse model (TGI = 73.6%, 50 mg/kg). Immunoassays suggested that 35j remarkably increased the infiltration of positive immune cells, thereby reinvigorating antitumor immunity. These results demonstrate that 35j is a potent CD73 inhibitor worthy of further development.

Impacts of age and BMI on vancomycin model choice in a Bayesian software: Lessons from a very large multi-site retrospective study.

Model-informed precision dosing (MIPD) optimizes drug doses based on pharmacokinetic (PK) model predictions, necessitating careful selection of models tailored to patient characteristics. This study evaluates the predictive performance of various vancomycin PK models across diverse age and BMI categories, drawing insights from a large multi-site database. Adults receiving vancomycin intravenous therapy at United States health systems between January 1, 2022, and December 31, 2023, were included. Patient demographics, vancomycin administration records, and therapeutic drug monitoring levels (TDMs) were collected from the InsightRX database. Age and body mass index (BMI)-based subgroups were formed to assess model performance, with predictions made iteratively. The optimal model for each age-BMI subgroup was chosen based on predefined criteria: models were filtered for mean percentage error (MPE) ≤ 20% and normalized root mean squared error (RMSE) < 8 mg/L, and then the most accurate among them was selected. A total of 384,876 treatment courses across 155 US health systems were analyzed, contributing 841,604 TDMs. Eleven models were compared, showing varying accuracy across age-BMI categories (41%-73%), with higher accuracy observed once TDMs were available for Bayesian estimates of individual PK parameters. Models performed more poorly in younger adults compared to older adults, and the optimal model differed depending on age-BMI categories and prediction methods. Notably, in the a priori period, the Colin model performed best in adults aged 18-64 years across most BMI categories; the Goti/Tong model performed best in the older, non-obese adults; and the Hughes model performed best in many of the obese categories. Our study identifies specific vancomycin PK models that demonstrate superior predictions across age-BMI categories in MIPD applications. Our findings underscore the importance of tailored model selection for vancomycin management, especially highlighting the need for improved models in younger adult patients. Further research into the clinical implications of model performance is warranted to enhance patient care outcomes.

Synthesis of a dehydrodieugenol B derivative as a lead compound for visceral leishmaniasis-mechanism of action and in vivo pharmacokinetic studies.

Leishmaniasis is a parasitic neglected tropical disease, affecting 12 million people. Available treatments present several limitations, with an increasing number of resistance cases. In the search for new chemotherapies, the natural product dehydrodieugenol B was used as a scaffold for the synthesis of a series of derivatives, resulting in the discovery of the promising analog [4-(4-(5-allyl-3-methoxy-2-((4-methoxybenzyl)oxy)phenoxy)-3-methoxybenzyl)morpholine, 1]. In this work, we investigated the effect of compound 1 on cell signaling in Leishmania (L.) infantum, culminating in cell death, as well as its immunomodulatory effect in the host cell. Additionally, we performed a pharmacokinetic profile study in an animal model. After treatment, compound 1 induced the alkalinization of acidocalcisomes and concomitant Ca2+ release in the parasite. These events may induce depolarization of the mitochondrial potential, with successive collapse of the bioenergetic system, leading to a reduction of ATP and reactive oxygen species (ROS) levels. The analysis of total proteins and protein profile by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) demonstrated that compound 1 also altered the parasite proteins after treatment. Transmission electron microscopy studies revealed ultrastructural damage to mitochondria; together, these data suggest that compound 1 may promote autophagic cell death. Additionally, compound 1 also induced an immunomodulatory effect in host cells, with a reduction of Th1 and Th2 cytokine response, characterizing an anti-inflammatory compound. The obtained pharmacokinetic profile in rats enhances the potential of the compound, with a mean plasma half-life (T1/2) of 21 h. These data reinforce the potential of compound 1 as a new lead for future efficacy studies.

A versatile inhibitory approach and molecular mechanism on cancer cells and cholinesterase enzymes: Synthesis, DFT, ADMET and molecular docking of thiadiazole and oxadiazole derivatives

This study presents a multi-routed research design featuring thiadiazole/ oxadiazole based Schiff base derivatives as potential inhibitors, targeting cancer and Alzheimer. Among thiadiazole based Schiff base derivatives, the excellent inhibition was exhibited by compound 1 (IC50 = 20.10 ± 1.1, 22.21 ± 1.03 and 26.23 ± 2.2 µM for HepG2 (liver cancer), MCF-7 (breast cancer) and W138 (lung cancer), respectively) in comparison to the standard Doxorubicin. Oxadiazole based compound 9 was also found with spellbinding efficacy (IC50 =15.20 ± 2.5, 19.13 ± 2.2 and 12.33 ± 3.4 µM for HepG2, MCF-7 and W138, respectively). Both compounds 1(IC50=3.10 ± 0.20 and 3.70 ± 0.10 µM against AChE and BuChE) and 9 (IC50=2.20 ± 0.10 and 2.80 ± 0.50 µM against AChE and BuChE) were also found as excellent anti-Alzheimer agents in comparison to reference donepezil. The outcomes of in vitro biological activity were further studied in silico via molecular docking, DFT and ADMET to elucidate the binding interactions, stability, reactivity and pharmacokinetic profiles of potent compounds.

Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan.

Anti-drug antibodies (ADAs) generated in response to biopharmaceuticals can significantly impact pharmacokinetics (PK) and overall drug efficacy. Thus, the ICH M4 guidelines mandate summarizing immunogenicity data from clinical trials in drug approval applications. However, following the approval of the first antibody drug in Japan in 2001, no cross-sectional investigation has focused on immunogenicity during the regulatory review process. Therefore, this study aims to examine the review reports and prescribing information of antibody drugs approved in Japan to identify key points related to immunogenicity evaluation. We conducted a cross-sectional analysis of review reports for antibody drugs approved between June 2001 and July 2022 by the Japanese regulatory authority. Specifically, we evaluated the ADA positivity rate, presence of neutralizing antibodies, antibody titers, and effects of ADA on PK, efficacy, and safety. We also compared this information with that provided in the prescribing information. Our analysis revealed that the ADA positivity rate and its effects on PK, efficacy, and safety were critical aspects of the review process. The emphasis on these factors varied depending on the number of applications and disease area. The information presented in the prescribing information was largely consistent with that discussed in the review reports. Overall, this study provides the first cross-sectional evaluation of immunogenicity considerations in the regulatory review of antibody drugs in Japan. Our findings can contribute to the efficiency of clinical trial planning and preparation of approval applications, to potentially improve the overall drug development process and address the drug loss problem in Japan.

A loading dose of clofazimine to rapidly achieve steady-state-like concentrations in patients with nontuberculous mycobacterial disease.

Clofazimine is a promising drug for the treatment of nontuberculous mycobacterial (NTM) diseases. Accumulation of clofazimine to reach steady-state plasma concentrations takes months. A loading dose may reduce the time to steady-state-like concentrations. We evaluated the pharmacokinetics (PK), safety and tolerability of a loading dose regimen in patients with NTM disease. Adult participants received a 4-week loading dose regimen of 300 mg clofazimine once daily, followed by a maintenance dose of 100 mg once daily (combined with other antimycobacterial drugs). Blood samples for PK analysis were collected on three occasions. A population PK model for clofazimine was developed and simulations were performed to assess the time to reach steady-state-like (target) concentrations for different dosing regimens. Twelve participants were included. The geometric mean peak and trough clofazimine concentrations after the 4-week loading phase were 0.87 and 0.50 mg/L, respectively. Adverse events were common, but mostly mild and none led to discontinuation of clofazimine. Our loading dose regimen reduced the predicted median time to target concentrations by 1.5 months compared to no loading dose (3.8 versus 5.3 months). Further time benefit was predicted with a 6-week loading dose regimen (1.4 versus 5.3 months). A 4-week loading dose regimen of 300 mg once daily reduced the time to target clofazimine concentrations and was safe and well-tolerated. Extending the loading phase to 6 weeks could further decrease the time to target concentrations. Using a loading dose of clofazimine is a feasible strategy to optimize treatment of NTM disease. NCT05294146.

Immunogenicity dynamics and covariate effects after satralizumab administration predicted with a hidden Markov model.

Immunogenicity is the propensity of a therapeutic protein to generate an immune response to itself. While reporting of antidrug antibodies (ADAs) is increasing, model-based analysis of such data is seldom performed. Model-based characterization of factors affecting the emergence and dissipation of ADAs may inform drug development and/or improve understanding in clinical practice. This analysis aimed to predict ADA dynamics, including the potential influence of individual covariates, following subcutaneous satralizumab administration. Satralizumab is a humanized IgG2 monoclonal recycling IL-6 receptor antagonist antibody approved for treating neuromyelitis optica spectrum disorder (NMOSD). Longitudinal pharmacokinetic (PK) and ADA data from 154 NMOSD patients in two pivotal Phase 3 studies (NCT02028884, NCT02073279) and PK data from one Phase 1 study (SA-001JP) in 72 healthy volunteers were available for this analysis. An existing population PK model was adapted to derive steady-state concentration without ADA for each patient. A mixed hidden Markov model (mHMM) was developed whereby three different states were identified: one absorbing Markov state for non-ADA developer, and two dynamic and inter-connected Markov states-transient ADA negative and positive. Satralizumab exposure and body mass index impacted transition probabilities and, therefore, the likelihood of developing ADAs. In conclusion, the mHMM model was able to describe the time course of ADA development and identify patterns of ADA development in NMOSD patients following treatment with satralizumab, which may allow for the formulation of strategies to reduce the emergence or limit the impact of ADA in the clinical setting.

Metal Complexation for the Rational Design of Gemcitabine Formulations in Cancer Therapy.

Nanoformulation of chemotherapies represents a promising strategy to enhance outcomes in cancer therapy. Gemcitabine is a chemotherapeutic agent approved by the Food and Drug Administration for the treatment of various solid tumors. Nevertheless, its therapeutic effectiveness is constrained by its poor metabolic stability and pharmacokinetic profile. Nanoformulations of gemcitabine in lipid and polymer nanocarriers usually lead to poor loading capability and an inability to effectively control its release profile due to the physicochemical characteristics of the drug and matrices. Here, we propose metal-gemcitabine complexation with biorelevant metal cations as a strategy to alter the properties of gemcitabine in a noncovalent manner, paving the way for the development of novel nanoformulations. A speciation study on gemcitabine and Mn2+, Zn2+, and Ca2+ was performed with the aim of investigating the extent of the interaction between the drug and the proposed metal cations, and selecting the best conditions of temperature, pH, and drug-to-metal molar ratio that optimize such interactions. Also, a series of density functional theory calculations and spin-polarized ab initio molecular dynamics simulations were carried out to achieve insights on the atomistic modalities of these interactions. Mn2+-gemcitabine species demonstrated the ability to maintain gemcitabine's biological activity in vitro. The scientific relevance of this study lies in its potential to propose metal-gemcitabine as a valuable strategy for developing nanoformulations with optimized quality target product profiles. The work is also clinically relevant because it will lead to improved treatment outcomes, including enhanced efficacy and pharmacokinetics, decreased toxicity, and new clinical possibilities for this potent therapeutic molecule.

Monte Carlo simulations of cefepime in children receiving continuous kidney replacement therapy support continuous infusions for target attainment

BackgroundSepsis is a leading cause of acute kidney injury requiring continuous kidney replacement therapy (CKRT) and CKRT can alter drug pharmacokinetics (PK). Cefepime is used commonly in critically ill children and is cleared by CKRT, yet data regarding cefepime PK and pharmacodynamic (PD) target attainment in children receiving CKRT are scarce, so we performed Monte Carlo simulations (MCS) of cefepime dosing strategies in children receiving CKRT.MethodsWe developed a CKRT “module” in the precision dosing software Edsim++. The module was added into a pediatric cefepime PK model. 1000-fold MCS were performed using six dosing strategies in patients aged 2–25 years and ≥ 10 kg with differing residual kidney function (estimated glomerular filtration rate of 5 vs 30 mL/min/1.73 m2), CKRT prescriptions, (standard-dose total effluent flow of 2500 mL/h/1.73 m2 vs high-dose of 8000 mL/h/1.73 m2), and fluid accumulation (0–30%). Probability of target attainment (PTA) was defined by percentage of patients with free concentrations exceeding bacterial minimum inhibitory concentration (MIC) for 100% of the dosing interval (100% fT > 1xMIC) and 4xMIC using an MIC of 8 mg/L for Pseudomonas aeruginosa.ResultsAssuming standard-dose dialysis and minimal kidney function, > 90% PTA was achieved for 100% fT > 1x MIC with continuous infusions (CI) of 100–150 mg/kg/day (max 4/6 g) and 4-h infusions of 50 mg/kg (max 2 g), but > 90% PTA for 100% fT > 4x MIC was only achieved by 150 mg/kg CI. Decreased PTA was seen with less frequent dosing, shorter infusions, higher-dose CKRT, and higher residual kidney function.ConclusionsOur new CKRT-module was successfully added to an existing cefepime PK model for MCS in young patients on CKRT. When targeting 100% fT > 4xMIC or using higher-dose CKRT, CI would allow for higher PTA than intermittent dosing.

Pharmacokinetics of intramuscular L-carvone in sheep.

To measure and model concentrations of the analgesic L-carvone, a natural component of spearmint, over time when administered IM to sheep and to characterize L-carvone's effects on CBCs and clinical biochemistry panels. L-carvone formulated as a 50% solution (v/v) in ethanol and propylene glycol was administered at 71.6 mg/kg IM, split between each semitendinosus muscle in 6 sheep. Venous blood was sampled over 24 hours, and plasma was separated by centrifugation. Additional blood was collected for CBC and serum biochemical analysis, and tissues were sampled after euthanasia. L-carvone concentrations in plasma and tissue homogenates were measured using HPLC-MS-MS. Plasma pharmacokinetic data were described using a nonlinear mixed effects model. Complete blood count and biochemistry data were compared to baseline values using repeated-measures ANOVA and Holm-Šidák tests (P < .05). Maximum plasma concentrations ranged from 0.28 to 1.93 µg/mL and occurred within 9 to 15 minutes after injection. Pharmacokinetics were best described using 2 compartments. Elimination half-life was 33.7 minutes and 390.2 minutes in the central and peripheral compartments, respectively. Mild increases in neutrophil count and significant increases in creatinine kinase and aspartate aminotransferase were associated with injection site myonecrosis. No physical examination, behavioral, or other clinically significant laboratory changes were noted. Intramuscular L-carvone exhibits rapid time to peak concentration, relatively slow plasma elimination, and low tissue concentrations after 24 hours. L-carvone exhibits a favorable pharmacokinetic profile for an analgesic drug. A new L-carvone formulation or administration route is needed to reduce inflammation and necrosis at the injection site.

Exploring Phytochemical Profile and Biological Activities of Callistemon viminalis (Sol. ex Gaertn.) G.Don ex Loudon) By In vitro and In silico Approaches.

Callistemon viminalis (Sol. ex Gaertn.) G.Don ex Loudon) (family: Myrtaceae) is used for its medicinal properties in treating various metabolic disorders. We investigated the chemical characterization and biological screening of the n-hexane extract of C. viminalis. The total phenolic content was (37.45±7.40 mg GA.E/g D.E±S.D) and the total flavonoid content was (18.43±6.34 mg R.E/g D.E±S.D). GC-MS screening of the n-hexane extract tentatively identified 70 bioactive phytochemicals. The maximum antioxidant potential (289.99±9.01 mg T.E/g D.E±S.D) was observed via the FRAP assay. Enzyme inhibition assays revealed that n-hexane extract of C. viminalis showed enzyme inhibition against the enzymes including α-glucosidase (6.9±0.13 mmol of ACA.E/g D.E±S.D); α-amylase (7.2±0.56 mmol of ACA.E/g D.E±S.D), urease (4.95±0.9 mg of TU.E/g D.E±S.D), acetylcholinesterase (2.9±0.08 mg GALA.E/g D.E±S.D), lipoxygenase (4.93±1.05 mg of Indo.E/g D.E±S.D) and tyrosinase (4.33±0.62 mg of KA.E/g D.E±S.D). The extract showed maximum antibacterial activity against Staphylococcus aureus (71.30±4.44 %) followed by Bacillus subtilis (68.55±2.70 %), Pseudomonas aeruginosa (57.86±6.02 %), and Salmonella typhi (53.90±5.05 %). Docking studies revealed good docking interactions between ligands and the studied enzymes, whereas ADME analysis revealed the pharmacokinetic profiles of the phytoconstituents. C. viminalis possesses promising therapeutic potential and can be further explored for drug development and drug design.

Application of machine-learning models to predict the ganciclovir and valganciclovir exposure in children using a limited sampling strategy.

Intravenous ganciclovir and oral valganciclovir display significant variability in ganciclovir pharmacokinetics, particularly in children. Therapeutic drug monitoring currently relies on the area under the concentration-time (AUC). Machine-learning (ML) algorithms represent an interesting alternative to Maximum-a-Posteriori Bayesian-estimators for AUC estimation. The goal of our study was to develop and validate an ML-based limited sampling strategy (LSS) approach to determine ganciclovir AUC0-24 after administration of either intravenous ganciclovir or oral valganciclovir in children. Pharmacokinetic parameters from four published population pharmacokinetic models, in addition to the World Health Organization growth curve for children, were used in the mrgsolve R package to simulate 10,800 pharmacokinetic profiles of children. Different ML algorithms were trained to predict AUC0-24 based on different combinations of two or three samples. Performances were evaluated in a simulated test set and in an external data set of real patients. The best estimation performances in the test set were obtained with the Xgboost algorithm using a 2 and 6 hours post dose LSS for oral valganciclovir (relative mean prediction error [rMPE] = 0.4% and relative root mean square error [rRMSE] = 5.7%) and 0 and 2 hours post dose LSS for intravenous ganciclovir (rMPE = 0.9% and rRMSE = 12.4%). In the external data set, the performance based on these two sample LSS was acceptable: rMPE = 0.2% and rRMSE = 16.5% for valganciclovir and rMPE = -9.7% and rRMSE = 17.2% for intravenous ganciclovir. The Xgboost algorithm developed resulted in a clinically relevant individual estimation using only two blood samples. This will improve the implementation of AUC-targeted ganciclovir therapeutic drug monitoring in children.

Computational Evaluation of Bioactive Compounds in Vernonia Amygdalina as a Novel Therapeutics for Acute Myeloid Leukemia: Targeting the Hedgehog Pathway

AbstractThe drug resistance challenges in acute myeloid leukemia have been linked the hedgehog (HH) signaling pathway activation by many studies. Furthermore, studies have shown that the components of the HH pathway, including 12‐pass transmembrane receptor Patched (PTCH), the 7‐pass transmembrane signal transduction protein Smoothened (SMO), and all three GLI transcription factors, are expressed in AML. Thus, pharmacological inhibition of SMO in the HH signaling in these cells has anti‐leukemic effects. However, the first SMO inhibitor specific to AML (Glasdegib) has been approved based on improved overall survival rates, but alternative approaches are still required. Thus we employed druglikeness screening, molecular docking, molecular dynamics simulation, non‐equilibrium free energy and in silico pharmacokinetics profiling on bioactive compounds from Vernonia amygdalina against SMO protein target. From 30 bioactive compounds in V. amygdalina, 13 had drug‐like potential, 5 had binding energy between −9.2 to −9.9 kcal/mol. Cryptolepine, neocryptolepine and isocryptolepine with the least BE showed good stability, dynamics over 300 ns of MD run and higher binding affinities via the Jarzynski's identity. Hence, these bioactive compounds may serve as potential drugs for the treatment of acute myeloid leukemia by targeting the SMO protein after wet lab experiments.

NEK10 kinase ablation affects mitochondrial morphology, function and protein phosphorylation status

BackgroundNEK10, a serine/threonine/tyrosine kinase belonging to the NEK (NIMA-related kinases) family, has been associated with diverse cellular processes. However, no specific target pathways have been identified. Our previous work knocking down NEK10 in HeLa cells suggested a functional association with mitochondria, as we observed altered mitochondrial morphology, mitochondrial oxygen consumption, mtDNA integrity, and reactive oxygen species levels.MethodsTo better understand this association, we studied human HAP1 cells fully knockout for NEK10 and confirmed that NEK10 has an important role in mitochondrial homeostasis.We performed the study of mitochondrial respiration, mitochondrial morphology, mitochondrial mass, and mtDNA analysis. Additionally, we showed proteome and phosphoproteome data of crude mitochondrial fraction of Parental and NEK10 KO cells using liquid chromatography-mass spectrometry (LC–MS/MS).ResultsIn the absence of NEK10 several mitochondrial functions were disturbed. Moreover, proteome and phosphoproteome analyses of mitochondrial fractions showed that NEK10 alters the threonine phosphorylation status of several mitochondrial/endoplasmic reticulum components, including HSP60, NDUFB4, and TOM20. These changes impacted the steady-state levels of a larger group of proteins, preferentially involving respiratory complexes and autophagy pathways.ConclusionWe concluded that NEK10 plays a key role in mitochondrial function, possibly by modulating the phosphorylation status of mitochondrial proteins.

A randomized phase I study of BI 1820237, a novel neuropeptide Y receptor type 2 agonist, alone or in combination with low-dose liraglutide in otherwise healthy men with overweight or obesity.

Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight. This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD. In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m2) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying. BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive.

Stiff-Soft Hybrid Biomimetic Nano-Emulsion for Targeted Liver Delivery and Treatment of Early Nonalcoholic Fatty Liver Disease

Background: Nonalcoholic fatty liver disease (NAFLD) poses a risk for numerous metabolic diseases. To date, the U.S. Food and Drug Administration has not yet approved any medications for the treatment of NAFLD, for which developing therapeutic drugs is urgent. Dihydromyricetin (DMY), the most abundant flavonoid in vine tea, has been shown to be hepatoprotective. Its application was limited by low bioavailability in vivo; Methods: In order to improve the bioavailability of DMY and achieve liver-targeted delivery, we designed a DMY-loaded stiff-soft hybrid biomimetic nano drug delivery system (DMY-hNE). The in vivo absorption, distribution, pharmacokinetic profiles, and anti-NAFLD efficacy of DMY-hNE were studied; Results: DMY-hNE was composed of a stiff core and soft shell, which led to enhanced uptake by gastrointestinal epithelial cells and increased penetration of the mucus barrier, thus improving the in vivo absorption, plasma DMY concentration, and liver distribution versus free DMY. In an early NAFLD mouse model, DMY-hNE effectively ameliorated fatty lesions accompanied with reduced lipid levels and liver tissue inflammation; Conclusions: These findings suggested that DMY-hNE is a promising platform for liver drug delivery and treatment of hepatopathy.

Tumoral Pharmacokinetic-Pharmacodynamic Simulation of Doxorubicin-Encapsulated Polymeric Micelles Using a Tissue-Isolated Tumor Perfusion System.

Pharmacokinetic (PK) elucidation of polymeric micelles delivering anticancer drugs is crucial for accurate antitumor PK-pharmacodynamic (PK-PD) simulations. Particularly, establishing a methodology to quantify the tumor inflow and outflow of anticancer drugs encapsulated in polymeric micelles is an essential challenge. General tumor biodistribution experiments are disadvantageous in that inflow quantification is easy, but outflow quantification is challenging. We addressed this issue by proposing a quantification method that combines a tissue-isolated tumor perfusion system with microdialysis. This method aims to determine tumoral drug inflow and outflow by quantifying the drugs released from the polymeric micelles via a tumor-embedded microdialysis probe and perfusate, respectively. Furthermore, we evaluated the feasibility of this method by perfusing pH-sensitive polyethylene glycol-poly(aspartate-hydrazone-doxorubicin/phenylalanine)n (PPDF-Hyd-DOX) in a tissue-isolated tumor perfusion system, and we quantified tumor inflow and outflow released DOX. Based on the quantitative results, we performed compartmental analyses by incorporating the gamma-distributed delay function and calculated the PK rate constants. These parameters were input into a tumor-bearing rat compartment model for ex vivo-in vivo extrapolation (EVIVE) of the rat plasma PPDF-Hyd-DOX concentrations and simulated intratumorally released DOX concentrations. The simulation profiles demonstrated a good fit with the Walker 256 intratumoral released DOX concentration profiles previously reported. This EVIVE-PK model was coupled with the threshold natural-growth tumor PD model, and PK-PD analysis was performed. This model exhibited a better fit to the tumor weight profile of Walker 256-bearing rats treated with PPDF-Hyd-DOX than that of our previously reported PK-PD model. Thus, EVIVE, based on a tissue-isolated tumor perfusion system with microdialysis, is a promising approach for the PK-PD simulation of polymeric micelle anticancer therapy.

Prediction of tissue exposures of polymyxin-B, amikacin and sulbactam using physiologically-based pharmacokinetic modeling.

The combination antimicrobial therapy consisting of amikacin, polymyxin-B, and sulbactam demonstrated in vitro synergy against multi-drug resistant Acinetobacter baumannii. The objectives were to predict drug disposition and extrapolate their efficacy in the blood, lung, heart, muscle and skin tissues using a physiologically-based pharmacokinetic (PBPK) modeling approach and to evaluate achievement of target pharmacodynamic (PD) indices against A. baumannii. A PBPK model was initially developed for amikacin, polymyxin-B, and sulbactam in adult subjects, and then scaled to pediatrics, accounting for both renal and non-renal clearances. The simulated plasma and tissue drug exposures were compared to the observed data from humans and rats. Efficacy was inferred using joint probability of target attainment of target PD indices. The simulated plasma drug exposures in adults and pediatrics were within the 0.5 to 2 boundary of the mean fold error for the ratio between simulated and observed means. Simulated drug exposures in blood, skin, lung, and heart were consistent with reported penetration ratio between tissue and plasma drug exposure. In a virtual pediatric population from 2 to <18 years of age using pediatric dosing regimens, the interpretive breakpoints were achieved in 85-90% of the population. The utility of PBPK to predict and simulate the amount of antibacterial drug exposure in tissue is a practical approach to overcome the difficulty of obtaining tissue drug concentrations in pediatric population. As combination therapy, amikacin/polymyxin-B/sulbactam drug concentrations in the tissues exhibited sufficient penetration to combat extremely drug resistant A. baumannii clinical isolates.

Spesolimab, the first-in-class anti-IL-36R antibody: From bench to clinic.

Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/β/γ, and at least one endogenous antagonist, IL-36R antagonist. Invitro and invivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need.

Design, synthesis, in vitro, and in silico study of benzothiazole-based compounds as a potent anti-Alzheimer agent.

Alzheimer's disease (AD) is a multifactorial neurological disorder that involves multiple enzymes in the process of developing. Conventional monotherapies provide relief, necessitating alternative multi-targeting approaches to address AD complexity. Therefore, we synthesize N-(benzo[d]thiazol-2-yl) benzamide-based compounds and tested against monoamine oxidases (MAO-A and MAO-B). In the in vitro experimental evaluation of MAO, all the compounds displayed remarkable potency, having IC50 values in the lower micromolar range. The most potent MAO-A inhibitor was (3e) with an IC50 value of 0.92 ± 0.09μM, whereas, (3d) was the most potent inhibitor of MAO-B with an IC50 value of 0.48 ± 0.04μM. Moreover, Enzyme kinetics studies revealed that the potent inhibitors of MAO-A and MAO-B showed competitive mode of inhibition. Furthermore, molecular docking studies were also performed to confirm the mode of inhibition and obtain an intuitive picture of potent inhibitors. It also revealed several important interactions, particularly hydrogen bonding interaction. All the newly synthesized compounds showed good ADME pharmacokinetic profile and followed Lipinski rule; these compounds represent promising hits for the development of promising lead compounds for AD treatment.