Pharmacokinetic Studies Research Articles

Introduction to Instruments used in Pharmacology with its Application

Pharmacology is a multidisciplinary field that focuses on the study of drug interactions, mechanisms of action, and therapeutic effects. The advancement of pharmacological research and clinical applications is heavily dependent on various specialized instruments that enable precise measurement, analysis, and monitoring of drug properties and their effects on biological systems. Instruments used in pharmacology range from simple laboratory tools, such as spectrophotometers and chromatographs, to more complex systems like high chromatography (HPLC), mass spectrometry (MS), and in vivo imaging devices. These tools are essential for drug discovery, pharmacokinetic studies, dose assessments, and toxicological evaluations. The development and application of these instruments allow researchers to accurately quantify drug concentrations, monitor physiological changes, and identify potential drug targets, thereby facilitating the discovery of safe and effective pharmaceutical agents. This introduction provides an overview of the fundamental instruments commonly used in pharmacology and highlights their critical roles in modern drug development and research..

Benzocarbazoledinones as SARS-CoV-2 Replication Inhibitors: Synthesis, Cell-Based Studies, Enzyme Inhibition, Molecular Modeling, and Pharmacokinetics Insights

Endemic and pandemic viruses represent significant public health challenges, leading to substantial morbidity and mortality over time. The COVID-19 pandemic has underscored the urgent need for the development and discovery of new, potent antiviral agents. In this study, we present the synthesis and anti-SARS-CoV-2 activity of a series of benzocarbazoledinones, assessed using cell-based screening assays. Our results indicate that four compounds (4a, 4b, 4d, and 4i) exhibit EC50 values below 4 μM without cytotoxic effects in Calu-3 cells. Mechanistic investigations focused on the inhibition of the SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) have used enzymatic assays. Notably, compounds 4a and 4b showed Mpro inhibition activity with IC50 values of 0.11 ± 0.05 and 0.37 ± 0.05 µM, respectively. Furthermore, in silico molecular docking, physicochemical, and pharmacokinetic studies were conducted to validate the mechanism and assess bioavailability. Compound 4a was selected for preliminary drug-likeness analysis and in vivo pharmacokinetics investigations, which yielded promising results and corroborated the in vitro and in silico findings, reinforcing its potential as an anti-SARS-CoV-2 lead compound.

Dosing, Toxicity and Drug Concentrations for Ganciclovir/Valganciclovir in Preterm and Low Birthweight Infants Treated for Cytomegalovirus

Background: There is a lack of data regarding suitable dosage when administering intravenous ganciclovir (GCV) or oral valganciclovir (valGCV) to preterm and low birthweight infants with cytomegalovirus (CMV) disease. Methods: Data were collected for infants born before 32 weeks gestation and/or weighing less than 1.8 kg treated for CMV disease with GCV or valGCV between 2016 and 2023. Results: Twenty-four infants (58% males and 48% Asian ethnicity) with a median gestation of 31 weeks [interquartile range (IQR): 26.6–36.1], median weight of 950 g (IQR: 470–1692) and median age of 45 days (IQR: 6–84) at initiation of treatment were included. Seventeen infants were treated for symptomatic postnatal CMV and 7 for symptomatic congenital CMV. Most infants receiving GCV had 6 mg/kg twice daily dosing and most receiving valGCV had 16 mg/kg twice daily dosing. Fourteen infants had drug concentrations measured with combined geometric mean minimum blood plasma concentration (Cmin) of 2.44 mg/L and maximum blood plasma concentration of 7.98 mg/L for doses of 6 mg/kg GCV and 16 mg/kg valGCV, which is higher compared with term infants. The estimated area under the curve at 12 hours (AUC0–12h) was 54.34 mg × h/L, which doubled the value for term infants in a previous study. Notably, AUC0–12h had an inverse relationship with gestational age and weight. Infants with lower gestation and higher Cmin showed a higher tendency for more than 1 adverse effect. Conclusions: GCV and valGCV use among preterm and very low birthweight infants with CMV disease resulted in a higher incidence of adverse events, increased AUC0–12h and elevated Cmin compared with term infants. Further pharmacokinetic studies are necessary to determine the ideal dosage in this population.

The Impact of Dexamethasone and Prednisone on Apixaban and Rivaroxaban Exposure in COVID‐19 Patients: A Physiologically Based Pharmacokinetic Modeling Study

Dexamethasone (DEX) is currently the treatment of choice for patients with oxygen‐dependent COVID‐19. It has been observed, primarily in vitro, that dexamethasone induces the expression of CYP3A and the ABCB1 gene, which encodes P‐glycoprotein (P‐gp). This has raised concerns about potential interactions between DEX and substrates of CYP3A and P‐gp, such as direct oral anticoagulants (DOAC). Currently, there is limited robust evidence to support a clinically significant interaction between DEX and DOAC. Using physiologically based pharmacokinetic modeling (PBPK), we investigated the impact of DEX administered in the context of SARS‐CoV‐2 infection on the pharmacokinetics of apixaban (APX) and rivaroxaban (RVX). After validating the induction effect of the DEX compound on two CYP3A4 substrates using the limited available studies, we optimized the compound in a COVID‐19 patient population, where significantly higher DEX plasma concentrations were observed compared to healthy volunteers. Our PBPK‐based PK simulations showed a 20% decrease in the AUC of APX and RVX in a worst‐case scenario and when DEX was administered at 6 mg PO for 10 days. This finding confirms the limited clinical data currently available and supports the use of APX and RVX with DEX in COVID‐19 patients at low‐risk for thrombo‐embolism. In addition, our results suggest that prednisone (PRED), when used at an equipotent dose, could serve as a viable alternative to DEX, given its less pronounced induction effect on APX and RVX. Further research is needed to validate these findings and to explore the clinical implications of using PRED in place of DEX in such scenarios.

Novel analytical approach for baclofen quantification in rodent plasma

AbstractA simple, accurate, and robust reverse‐phase high‐performance liquid chromatography (RP‐HPLC) method was developed and validated for the quantification of Baclofen in rat plasma. The method demonstrated high degree of linearity (r2 = 0.9936) across a concentration range of 10–50 μg/mL. Precision, accuracy, limit of detection (LOD), limit of quantification (LOQ), and robustness were evaluated according to ICH guidelines. The LOD and LOQ were found to be 0.076197 and 0.23090 μg/mL, respectively. This method provides an efficient approach for Baclofen quantification in plasma, making it suitable for pharmacokinetic and bioavailability studies. The novelty of this study lies in its optimization for routine use in laboratories, ensuring reproducibility with minimal variations across different conditions and analysts.

Abstract 4116177: Metabolic and Pharmacokinetic Profiling of Ketone Ester by Background SGLT2 Inhibitor Therapy in Heart Failure with Reduced Ejection: A Phase I Clinical Trial

Background: Growing evidence supports a therapeutic role for ketones in HFrEF. However, no pharmacokinetic (PK) studies are available to guide further investigation, and uncertainty exists regarding use with the ketogenic SGLT2i and dose-dependent effects. Methods: We conducted a phase I trial of two doses of ketone ester (KE, 250 mg/kg and 500 mg/kg) in 20 HFrEF participants, stratified by SGLT2i use. Non-compartmental analysis assessed PK parameters of ketones. Paired t-tests and generalized linear mixed models assessed changes in mass-spectrometry based targeted metabolites, blood gas, and vital sign assessments up to 4 hours after dosing. Results: The mean age was 66.0±14.8 years, 45% were women, 30% were non-White, and average EF was 33±13%. The median (25 th –75 th percentile) T max , C max , and T 1/2 for total ketones with 250 and 500 mg/kg doses were 1.01 (0.64-1.24) and 1.58 (1.06-1.99) hours, 2317 (2165-2491) and 3354 (3291-3538) µM, and 0.85 (0.66-1.24) and 2.04 (1.36-3.47) hours, respectively ( Figure 1A ). One hour after KE consumption, insulin levels robustly increased, while non-esterified fatty acids, branched-chain amino acids, and acylcarnitines decreased except for C2/C4-OH acylcarnitines, which increased (FDR-adjusted p-value<0.05). Increases in ketones and C2/C4-OH acylcarnitines were dose-dependent, while background SGLT2i was associated with blunting of the decrease across acylcarnitines. One hour post KE, heart rate initially rose by 4 (95%CI 2-6) beats/min, while systolic blood pressure (-7, 95%CI -12, -2 mmHg), pH (-0.07, 95%CI -0.08, 0.05), and bicarbonate (-3, 95%CI -4, -2 mEq/L) decreased, with dose-dependent acid-based effects ( Figures 1B-C ). These values returned close to baseline by 4 hours. Adverse events were infrequent and mild. Conclusions: Acute KE ingestion is associated with rapid changes in several key metabolic pathways, with differential effects imparted by background SGLT2i (fatty acid metabolism) and dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose/SGLT2i, while acidotic effects were heightened with increasing dose. These data support the safety of combined KE and SGLT2i in HFrEF and provide grounding data for further trials.

Advancements in breast cancer management: a comprehensive review of ribociclib combined with endocrine therapy

Background: In this review, the complicated landscape of breast cancer management is explored with a focus on the promising synergies between ribociclib and endocrine therapy. Ribociclib mainly acts as a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, which disrupts cell cycle progression necessary for tumor growth. This, in combination with endocrine therapy, aims to produce hormone receptor-positive breast cancers, which is a very relevant subtype with challenging therapeutics. Methods: A comprehensive review was conducted using multiple databases, PubMed, Embase, Scopus, Cochrane Library, and Web of Science, covering the period from January 1990 to May 2024. Results: Pharmacokinetic studies underscore the efficacy and tolerability of ribociclib, thus providing vital information for dose adjustments, particularly among patients with renal and hepatic impairments. Ribociclib’s value in extending progression-free survival and improving overall survival has been shown by clinical trials such as the MONALEESA series. Quality of life considerations and patient-reported outcomes from these trials indicate that ribociclib has a broader effect on the well-being of the patients. However, despite the success experienced by this drug in clinical practice, it still has some side effects, including hematologic toxicity, hepatotoxicity, and thromboembolism associated with it. Ribociclib resistance mechanisms are multifaceted mixtures comprising genetic variations or mutations, compensatory signaling pathways, and epigenomic changes. While overcoming resistance remains challenging, ongoing research seeks to reconcile. Conclusion: Ribociclib combined with endocrine therapy represents a significant advancement in breast cancer treatment, albeit with challenges that necessitate ongoing research and holistic patient care approaches.

Antimicrobial Pharmacokinetic Studies in Sea Turtles: A Review

ABSTRACTSea turtles face various threats to survival, primarily due to human activities, such as bycatch, vessel strikes, pollution, and climate change. Many of these activities can lead to illness or injuries, increasing the risk of infection. Treating infections appropriately and effectively requires knowledge of antimicrobial properties and their ability to eradicate microbes without harm to the sea turtle. Robust pharmacokinetic studies, therefore, are important for appropriate dosing. Herein, we review the studies detailing the pharmacokinetic properties of antimicrobials in sea turtles conducted to date.

Abstract 4135497: Model-informed dosing recommendations for digoxin in interstage single ventricle heart disease

Digoxin is commonly used in infants with single ventricle heart disease (SVD) and may decrease mortality in the interstage period. While labeled for the treatment of heart failure in infants, dosing recommendations do not account for alterations in drug disposition in SVD. We aimed to characterize digoxin pharmacokinetics (PK) in interstage infants with SVD. Infants <3 months with SVD who received enteral digoxin per standard of care after stage 1 and prior to stage 2 palliation were included in this prospective, multicenter, open-label PK study. Preterm infants and those with creatinine >2mg/dL or on extracorporeal support at enrollment were excluded. PK samples were prospectively collected and digoxin plasma concentrations quantitated by HPLC/MS/MS assay validated per FDA guidance. Population PK analysis was performed in NONMEM. Effects of covariates on PK parameters were evaluated. Dosing simulations were conducted in a virtual cohort of infants with SVD that optimized dosing to achieve trough concentrations of 0.5-2 ng/mL, the label-endorsed reference range for heart failure. Across 10 sites, 50 infants contributed 207 PK samples. Table 1 shows cohort characteristics. A 2-compartment model with transit compartment absorption and linear elimination best described the data. Renal function and weight were significant covariates. Infants with SVD had lower apparent clearance than previously reported in infants without SVD. Current labeled dosing resulted in simulated exposures above the reference range ( Figure 1 ). A new dosing regimen for infants with SVD is proposed. Digoxin PK is altered in infants with SVD. Dosing should account for renal function, age, and weight.

CTNI-60. SAFETY LEAD-IN RESULTS FOR QBS10072S IN THE INDIVIDUAL SCREENING TRIAL OF INNOVATIVE GLIOBLASTOMA THERAPY (INSIGHT) TRIAL, A RANDOMIZED ADAPTIVE PLATFORM TRIAL FOR NEWLY DIAGNOSED MGMT UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND QBS10072S, is a L-type amino acid transporter 1 (LAT-1) targeted alkylating agent that utilizes LAT1 as both a transport and targeting mechanism. QBS10072S can cross the blood-brain barrier, exhibits potential for cytotoxicity with a mechanism distinct from temozolomide and has low off-target effects. QBS10072S is being evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial (NCT02977780), a randomized phase 2 adaptive multi-arm platform trial. METHODS Adult patients with newly diagnosed MGMT-unmethylated glioblastoma are eligible for INSIGhT. Since there is no safety data available for QBS10072S in combination with radiotherapy, a safety lead-in evaluation was conducted utilizing a 3 + 3 design. Starting dose for QBS10072S was 12mg/m2 in combination with radiation therapy and adjuvantly as monotherapy in 28 day cycles. Patients were monitored for dose-limiting toxicities (DLTs) to identify the maximum tolerated dose and recommended phase 2 dose (RP2D). RESULTS Nine patients were enrolled December 2022 to October 2023 for safety lead-in testing, and median age was 57 years (41-67) with 6 (66%) males, 6 (66%) patients with gross total resection, and median KPS 90 (range 80-100). Pharmacokinetic studies indicated that drug exposure was lower than prior studies, and three patients received 12mg/m2, 15mg/m2, and 18mg/m2, respectively, per dose escalation protocol. No DLTs nor adverse events leading to study drug discontinuation were reported during the evaluation period. Four patients had possible treatment-related CTCAE grade ≥ 3 toxicity including lymphopenia (n=3) and fatigue (n=1). The RP2D was determined to be 18mg/m2. Seven patients were discontinued from study treatment due to progressive disease and two patients remain on treatment. CONCLUSION QBS10072S, concurrent and adjuvant to radiation therapy, was well-tolerated in patients with newly diagnosed unmethylated MGMT glioblastoma. QBS10072S 18mg/m2 is being evaluated as a treatment arm in phase 2 testing in the ongoing INSIGhT trial.

Studying the Role of Novel Carbon Nano Tubes as a Therapeutic Agent to Treat Triple Negative Breast Cancer (TNBC) - an In Vitro and In Vivo Study

Triple Negative Breast Cancer (TNBC) is a malignant cancer with a very high mortality rate around the world. African American(AA) women are 28% more likely to die from triple-negative breast cancer (TNBC) than white women with the same diagnosis. AA patients are also more likely to be diagnosed at a later stage of the disease and have the lowest survival rates for any stage of diagnosis; There are very few existing anti TNBC drugs with therapeutic efficacy hence newer anti TNBC drug design and investigation is needed. Carbon Nano Tubes(CNT) in recent years have shown effective anti-cancer properties in various types of cancers as reported in peer reviewed journals. Henceforth, we did an investigation to study the anticancer properties of a novel CNT in both in vitro and in vivo models of TNBC. We tested the CNT drug in vitro cytotoxicity studies on TNBC model MDA-MB-231 VIM RFP cell lines and Spheroid forming assays on the same cancer cells; we also did an in vivo study on TNBC model mice to study the therapeutic efficacy of this CNT drug in reducing the tumor load. Our initial studies showed increased cell death and reduction in spheroid numbers in the CNT treated cancer cells in comparison to control and a significant reduction in the tumor volume in the TNBC model mice than in untreated animals. Thus our initial studies have shown significant therapeutic efficacy of the novel CNT as an anti TNBC agent. Additional mechanistic studies need to be done to find out the cell death mechanisms, core canonical pathways involved, pharmacokinetic studies before translational research for this novel nanoparticle as a therapeutic agent from bench to bedside.

FDA and EMA Oversight of Disruptive Science on Application of Finite Absorption Time (F.A.T.) Concept in Oral Drug Absorption: Time for Scientific and Regulatory Changes

Background: It has been demonstrated that the concept of infinite absorption time, associated with the absorption rate constant, which drives a drug’s gastrointestinal absorption rate, is not physiologically sound. The recent analysis of oral drug absorption data based on the finite absorption time (F.A.T.) concept and the relevant physiologically based finite-time pharmacokinetic (PBFTPK) models developed provided a better physiologically sound description of oral drug absorption. Methods: In this study, we re-analyzed, using PBFTPK models, seven data sets of ketoprofen, amplodipine, theophylline (three formulations), and two formulations (reference, test) from a levonorgestrel bioequivalence study. Equations for one-compartment-model drugs, for the estimation of fraction of dose absorbed or the bioavailable fraction exclusively from oral data, were developed. Results: In all cases, meaningful estimates for (i) the number of absorption stages, namely, one for ketoprofen and the levonorgestrel formulations, two for amlodipine, the immediate-release theophylline formulation, and the extended-release Theotrim formulation, and three for the extended-release Theodur formulation, (ii) the duration of each absorption stage and the corresponding drug input rate, and (iii) the total duration of drug absorption, which ranged from 0.75 h (ketoprofen) to 11.6 h for Theodur were derived. Estimates for the bioavailable fraction of ketoprofen and two theophylline formulations exhibiting one-compartment-model kinetics were derived. Conclusions: This study provides insights into the detailed characteristics of oral drug absorption. The use of PBFTPK models in drug absorption analysis can be leveraged as a computational framework to discontinue the perpetuation of the mathematical fallacy of classical pharmacokinetic analysis based on the absorption rate constant as well as in the physiologically based pharmacokinetic (PBPK) studies and pharmacometrics. The present study is an additional piece of evidence for the scientific and regulatory changes required to be implemented by the regulatory agencies in the not-too-distant future.

Quantifying Withanolides in Plasma: Pharmacokinetic Studies and Analytical Methods

Withania somnifera (common name: ashwagandha; WS) is an Ayurvedic botanical that has become popular for its reputed effects on stress and insomnia. Research into the bioactive compounds responsible for the biological effects of WS has largely focused on withanolides, a group of steroidal lactones commonly found in the Solanaceae family. Until recently, however, it was unclear which, if any, withanolides were present in the plasma after the ingestion of WS products. The aim of this review is to summarize current knowledge regarding the plasma pharmacokinetics of withanolides found in WS and the analytical methods developed to detect them in plasma. Twenty studies (sixteen animal, four human) were identified in which isolated withanolides or withanolide-containing products were administered to animals or humans and quantified in plasma. Withanolides were commonly analyzed using reversed-phase liquid chromatography coupled to mass spectrometry. Plasma concentrations of withanolides varied significantly depending on the substance administered, withanolide dose, and route of administration. Plasma pharmacokinetics of withaferin A, withanolide A, withanolide B, withanoside IV, 12-deoxywithastramonolide, and withanone have been reported in rodents (Cmax range: 5.6–8410 ng/mL), while withaferin A, withanolide A, 12-deoxywithastramonolide, and withanoside IV pharmacokinetic parameters have been described in humans (Cmax range: 0.1–49.5 ng/mL).

Synthesis and evaluation of fluorinated piperazine‐hydroxyethylamine analogues as potential antiplasmodial candidates

In this manuscript, twenty‐one novel fluorinated piperazine‐hydroxyethylamine analogues were synthesized and tested against Plasmodium falciparum (Pf). Among tested compounds, two 13g and 14g exhibited promising inhibitory activity on Pf3D7 with IC50 values of 0.28 and 0.09 µM, respectively. Neither of the hits exhibited cytotoxicity on HepG2 cells up to 150 µM and Vero cells up to 20 µM. Compounds 13g and 14g were also evaluated against chloroquine‐resistant PfDd2 and displayed IC50 values of 0.11 and 0.10 µM, respectively. Next, 13g and 14g were administered to the Plasmodium berghei mice model at 30mg/kg intraperitoneally for four consecutive doses, which showed 25% and 50% reduction in the parasitemia load, respectively. The efficacy of hits 13g and 14g was improved along with mean survival time when administered in combination with artesunate. On liver‐stage parasites, compounds 13g and 14g showed >90% inhibition at 1µM. Compound 14g was also tested for toxicity in mice at 100 mg/kg dose, which revealed no abnormality in mice organs. Preliminary pharmacokinetic studies of compound 14g exhibited absorption and maintained a presence in the body for more than six hours.

A novel, sensitive, and fast ultra-high-performance liquid chromatography tandem mass spectrometry method for TNG908 determination in dog plasma and pharmacokinetic study.

TNG908 is a potent and selective protein arginase methyltransferase 5 (PRMT5) inhibitor that is currently going through phase I/II clinical development for the treatment of non-small cell lung cancer. To facilitate pharmacokinetic and toxicokinetic studies of TNG908, here, we reported an ultra-high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the detection of TNG908 in dogs. The dog plasma samples were precipitated by acetonitrile and analyzed using a Waters ACQUITY BEH C18 column combined with a Thermo triple quadrupole mass spectrometer. The mobile phase consisted of 0.1% formic acid solution and acetonitrile, at a flow rate of 0.3mL/min. TNG908 and internal standard were monitored by selective reaction monitoring (SRM) with m/z 410.2 > 150.1 and m/z 394.2 > 278.1, respectively. The method demonstrated excellent linearity over the concentration range of 1-1000 ng/mL, with a correlation coefficient greater than 0.995. Acetonitrile-mediated protein precipitation showed high extraction efficiency and a recovery above 80%. The validated assay was further applied to measure TNG908 in dog plasma after oral and intravenous administration and achieved success. The obtained pharmacokinetic parameters indicated low clearance of TNG908 (3.7 ± 0.8mL/min/kg) and moderate oral bioavailability (>36.4%).

OPTIMIZATION OF LC-MS/MS METHOD FOR THE SIMULTANEOUS DETERMINATION OF METFORMIN AND ROSIGLITAZONE IN HUMAN PLASMA WITH BOX-BEHNKEN DESIGN

Objective: The objective of this study was to develop a robust Liquid Chromatography – Tandem Mass Spectrometry (LC-MS/MS) methodology for the precise quantification of metformin and rosiglitazone in human plasma. Methods: A Design of Experiments (DOE) framework was utilized, specifically employing a Box-Behnken experimental design, to optimize critical parameters such as Capillary voltage, Cone voltage, Desolvation temperature, and Collision energy. Sample preparation involved protein precipitation using acetonitrile, simplifying the procedure. Chromatography was performed with a mobile phase of 0.1% formic acid and acetonitrile (60:40 V/V) to enhance sensitivity and reproducibility. Quantification was achieved through Multiple Reaction Monitoring (MRM) of the transition’s m/z 130.1 → m/z 60.1 for metformin, m/z 358.2 → m/z 134.9 for rosiglitazone, and m/z 206.3 → m/z 59.9 for phenformin. The methodology was validated according to regulatory guidelines. Results: The developed methodology demonstrated selectivity, linearity, accuracy, precision, recovery, and stability. The calibration curve showed linearity over the concentration range of 5 ng/ml to 1000 ng/ml for metformin and 1.5 ng/ml to 300 ng/ml for rosiglitazone. Accuracy and precision were within acceptable limits across calibration and quality control standards. Assessments of extraction recovery and matrix effects confirmed the robustness of the extraction procedure, with negligible interference from plasma components. Stability studies indicated that the method maintained acceptable limits for metformin and rosiglitazone concentrations under various storage and handling conditions. Conclusion: The validated Liquid Chromatography – Tandem Mass Spectrometry (LC-MS/MS) methodology provides a reliable and accurate platform for the quantification of metformin and rosiglitazone in human plasma. This method shows potential applications in pharmacokinetic studies and clinical research, ensuring consistent performance in routine analysis.

OPTIMIZED SOLID LIPID NANOPARTICLES FOR ENHANCED ORAL BIOAVAILABILITY AND OSTEOGENIC EFFECT OF IPRIFLAVONE: FORMULATION, CHARACTERIZATION, AND IN VITRO EVALUATION

Objective: This study aimed to enhance the oral bioavailability of Ipriflavone (IP) and evaluate its osteogenic effect on human osteosarcoma cells (MG-63) by developing Ipriflavone-loaded Solid Lipid Nanoparticles (IP-SLN). Methods: IP-SLNs were prepared using a modified solvent evaporation method with probe sonication. Formulation optimization employed Central Composite Design (CCD) with independent variables, including lipid amount, surfactant concentration, and sonication time. Characterization was performed using Transmission Electron Microscopy (TEM). In vitro drug release and ex vivo permeation studies were conducted to assess drug release kinetics and bioavailability. Cytotoxicity, Alkaline Phosphatase (ALP) activity, and calcium deposition studies on MG-63 cells evaluated osteogenic effects. Results: TEM images showed round particles with an average diameter of 43.24±3 nm, a zeta potential of-9.53 mV, and a drug entrapment efficiency of 76.53±1.84%. In vitro drug release from IP-SLN was 79.02% compared to 14.21% from IP after 48 h, following the Korsmeyer-Peppas model and first-order kinetics. Ex vivo permeation of IP-SLN was approximately 2-fold higher than IP dispersion. Cytotoxicity studies revealed no toxicity on MG-63 cells. ALP activity and calcium deposition studies indicated that IP-SLN stimulated osteoblast differentiation, increasing alkaline phosphatase activity and mineralization. Pharmacokinetic studies demonstrated that IP-SLN increased the relative bioavailability by 515% compared to ipriflavone. Conclusion: IP-SLN formulations significantly improved the oral bioavailability and osteogenic effects of ipriflavone on MG-63 cells, suggesting potential for novel therapeutic applications in osteoporosis treatment.

Population pharmacokinetic modeling of paired plasma-breast milk lamivudine data for estimation of infant exposure in breastfeeding mother-infant pairs.

Around 1.2 million women living with HIV give birth annually, majority of whom will breastfeed their infants while receiving antiretroviral therapy (ART). Lamivudine, a component of first-line ART regimens crosses from maternal plasma to breast milk, with measurable concentrations in some breastfed infants. Wide variability in plasma-to-breast milk transfer has been reported within- or across studies, probably due to differences in sampling framework. This work sought to characterize the milk-to-plasma transfer of lamivudine, quantify inter-patient variability and associated factors, and predict exposure of a breastfed infant. We explored data from an observational pharmacokinetic study that included 35 Ugandan mothers and their infants. Mothers received lamivudine doses of 150 mg twice daily or 300 mg once daily as part of their antiretroviral regimen. Pharmacokinetic sampling was undertaken across two visits approximately 8 weeks apart, providing 248 maternal plasma, 256 breast milk-, and 151 infant blood concentrations, measured across a 24-h sampling interval. A one-compartmental model best described the plasma disposition of lamivudine, with first-order absorption, interindividual variability on clearance and volume of distribution, and a proportional residual error model. A lag in time of plasma-to-breast milk drug accumulation was described using an effect compartment model with a milk-to-plasma ratio of 1.77. An estimated daily infant dose of 179.3 μg/kg (range: 125.8, 282.3) closely predicted the observed infant steady-state concentrations and translated into 3.34% (2.13, 7.20) and 3.35% (1.10, 7.15) of the standard daily maternal dose in visits 1 and 2, respectively. The established modeling framework can be extended to other drugs.

DeepCt: Predicting Pharmacokinetic Concentration-Time Curves and Compartmental Models from Chemical Structure Using Deep Learning.

After initial triaging using in vitro absorption, distribution, metabolism, and excretion (ADME) assays, pharmacokinetic (PK) studies are the first application of promising drug candidates in living mammals. Preclinical PK studies characterize the evolution of the compound's concentration over time, typically in rodents' blood or plasma. From this concentration-time (C-t) profiles, PK parameters such as total exposure or maximum concentration can be subsequently derived. An early estimation of compounds' PK offers the promise of reducing animal studies and cycle times by selecting and designing molecules with increased chances of success at the PK stage. Even though C-t curves are the major readout from a PK study, most machine learning-based prediction efforts have focused on the derived PK parameters instead of C-t profiles, likely due to the lack of approaches to model the underlying ADME mechanisms. Herein, a novel deep learning approach termed DeepCt is proposed for the prediction of C-t curves from the compound structure. Our methodology is based on the prediction of an underlying mechanistic compartmental PK model, which enables further simulations, and predictions of single- and multiple-dose C-t profiles.

Formulation and optimization of xanthohumol loaded solid dispersion for effective treatment of Parkinson's disease in rats: In vitro and in vivo assessment

Xanthohumol (XH) is a prenylated flavonoid that possesses neuroprotective effects by increasing the levels of dopamine (DA), reducing oxidative stress, and neuroinflammation against Parkinson's disease (PD). However, the neuroprotective efficacy of XH in managing PD is limited by its low solubility, poor bioavailability, and less blood-brain barrier (BBB) permeability leading to decreased therapeutic activity. To overcome these limitations, XH-loaded solid dispersion (SD) has been formulated using the Central Composite Design (CCD) approach. The optimized formulation was evaluated by determining the angle of repose, drug loading, percentage drug release, PXRD, DSC, FTIR, and SEM. The results of PXRD, DSC, and SEM demonstrated the formation of SD. The XH-SD showed a 6.45-fold enhancement in dissolution rate, a 12.7-fold increase in Cmax, and 26.11-fold increase in XH's area under curve (AUC) as compared to the naïve XH. In the pharmacokinetic studies, XH-SD showed a 42.20 folds increase in relative bioavailability(0-∞) compared to naïve XH. To assess pharmacodynamic effects, PD was induced using rotenone. The motor and non-motor functions were evaluated by assessing various behavioral parameters such as catalepsy, spontaneous locomotor activity and muscle coordination test. The formulation exhibited dose-dependent effects, with both low and high doses of XH-SD resulting in significant enhancements (P < 0.001) in motor functions in rats induced with PD. Furthermore, biochemical estimations showed that XH-SD at both doses increased the levels of dopamine (DA), and reduced oxidative stress and neuroinflammation.