Search Results (83)

RNA viruses with pandemic potential pose a significant global health risk. The adenosine nucleoside analog GS-441524 is metabolized to its active GS-443902 triphosphate metabolite to inhibit a broad spectrum of RNA viruses. Intravenous (IV) remdesivir (RDV) and oral obeldesivir (ODV) are phosphoramidate and isobutyryl-ester prodrugs of GS-441524, respectively. Following administration, both RDV and ODV show rapid and broad tissue distribution, form the same GS-443902 metabolite in target tissues, and demonstrate promising in vivo efficacy across several RNA virus infection models. In an African green monkey SARS-CoV-2 infection model, respective RDV and ODV treatments yielded similar antiviral efficacy. Here, we compare the in vitro and in vivo pharmacokinetics (PK) and metabolism of RDV and ODV to highlight both similarities and differences in their absorption, metabolism, distribution, and excretion profiles. The distinct route of administration and metabolic fate of each prodrug produced in vivo PK and metabolism profiles with differential GS-441524 to tissue GS-443902 relationships, thereby supporting alternate methods for predicting human efficacious doses. Overall, a metabolism-directed prodrug design enabled optimized delivery of the identical active GS-443902 metabolite through different routes of administration, supporting broader applications of the same nucleoside analog across an expanded spectrum of potential antiviral indications. Full article

The appropriate use of antibiotics is crucial and involves selecting an optimal dosing regimen based on pharmacokinetic (PK) and pharmacodynamic (PD) indicators. Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool that integrates drugs’ physicochemical properties with anatomical and physiological data to predict PK behavior. In pediatric populations, PBPK modeling accounts for developmental changes in organ function, making it particularly useful for optimizing antibiotic dosing across different age groups, from neonates to adolescents. In recent decades, PBPK modeling has been widely applied to predict antibiotic disposition in pediatric patients for various clinical and research purposes. Model-informed precision dosing (MIPD) is an evolving approach that enhances traditional therapeutic drug monitoring by integrating multiple information sources into a mathematical framework. By incorporating PBPK modeling, MIPD could offer a more optimized antibiotic dosing that accounts for PK/PD parameters at the site of infection, improving therapeutic outcomes while minimizing toxicity. This review summarizes currently published pediatric PBPK modeling studies on antibiotics, covering various objectives such as evaluating drug–drug interactions, PK/PD analyses in targeted tissues, predicting PK in specific populations (e.g., maternal/fetal, renal impairment, obesity), and PK predictions for preterm neonates. Based on these reports, the review discusses the implications of PBPK modeling for MIPD in pediatric antibiotic therapy. Full article

Background/Objectives: Haloxylon griffithii is a medicinal plant possessing therapeutic effects in disorders associated with the gastrointestinal (GIT) system. This research aims to study the pharmacological activity of Haloxylon griffithii in a multidimensional manner, involving phytochemistry screening and in vitro and in vivo experiments. Methods: The whole dried plant was extracted with 80% methanol and further fractionation using solvents of increasing polarity. GC-MS analysis was performed on the crude extract to discover volatile compounds. The spasmolytic/spasmogenic effect was assessed in isolated rabbit jejunum using spontaneous and K⁺-induced contractions, as well as contractions induced by increasing concentrations of calcium ions in depolarized tissue. Antidiarrheal activity was evaluated in Swiss albino rats/mice (n = 6/group) using castor oil-induced diarrhea and peristaltic index models. In silico ADMET screening was conducted via SwissADME and pkCSM. Results: The GC-MS profiling of H. griffithii revealed the presence of 59 phytochemicals and a rare azulene derivative and constituents, including α-santonin and hexadecanoic acid esters, with favorable pharmacokinetic profiles, as predicted using SwissADME and pkCSM computational tools. The in vitro and in vivo experiments revealed the significant calcium channel blocking activity in non-polar fractions (n-hexane and ethyl acetate), while the polar extracts (ethanolic, aqueous) exhibited cholinergic effects, indicating a dual mode of action. Conclusions: This was a first-time demonstration of both antidiarrheal and smooth muscle-relaxant activity in H. griffithii, supported by GC-MS profiling and pharmacological assay. The findings lend scientific credibility to the traditional use of the plant in community healthcare, while also reinforcing the need for further pharmacological and clinical studies to explore its potential in drug development. Full article

Background/Objectives: Exudative age-related macular degeneration (AMD) is a disease of choroidal neovascularization that causes blindness. Current treatments to preserve vision in this prevalent and blinding condition are repeat intraocular injections of anti-vascular endothelial growth factor medicines for a patient’s lifetime to preserve and prevent vision loss leading to blindness. Rifampicin, a small-molecule antibiotic, has previously been reported to exhibit anti-angiogenic properties and a topical safety profile that is well-tolerated. Based on this evidence, we investigated the feasibility of formulating rifamycin as an ophthalmic drop capable of delivering therapeutic concentrations to the posterior segment of the eye. Methods: Inhibition of neovascularization by administration of rifampicin was analyzed in the rat oxygen-induced retinopathy (OIR) and mouse laser-induced choroidal neovascularization (CNV) models. Pharmacokinetic (PK) studies were conducted in mice, rats, and rabbits by dosing various formulations containing rifampicin, and the compound was quantified by LC/MS analysis. Results: Results from dose escalation studies in the mouse laser-induced CNV model suggested the minimum effective dose of rifampicin required for inhibiting neovascularization in subretinal tissues to be 0.7 mg/kg, which is substantially lower than the 20 mg/kg dosage approved for infectious disease treatments. The previous studies did not report the minimum effective dose in the anti-angiogenesis effects. The effective area under the concentration-time curve (AUC) in the sub-retina was evaluated as 0.27 h·ng/mg. In rabbits, rifampicin was delivered to the sub-retina by a single topical application of various formulations in a dose-dependent manner. The topical application of the formulations containing 1% rifampicin, which was well-tolerated in clinical trials previously reported for ocular trachoma, achieved subretinal delivery approximately 2–32 times greater than the effective AUC. Plasma exposure of the compound by the topical application was evaluated to range approximately 0.5–10 ng/mL. Conclusions: Rifampicin was delivered to the sub-retina in rabbits with an efficiency greater than the effective dose required for inhibiting neovascularization. Limited amounts of plasma exposure by the topical application were detected. These results suggested the therapeutic potential of the rifampicin formulations for the topical treatment of exudative macular degeneration. Full article

Background: As a broad-spectrum fluoroquinolone, enrofloxacin (ENR) is commonly employed to manage bacterial infections in aquatic species. Nevertheless, there have been no documented pharmacokinetic and residue studies conducted on Dybowski’s frog (Rana dybowskii). Therefore, the objective of our study was to characterize the pharmacokinetics (PK) of ENR and its metabolite ciprofloxacin (CIP) in R. dybowskii, establish withdrawal times, and evaluate the physiological effects associated with ENR administration. Methods: Adult Rana dybowskii (120 individuals; 60 males and 60 females) were sex-separated and acclimated in four tanks. Prior to dosing, three males and three females were randomly selected as untreated controls (without ENR administration). Following the oral gavage of ENR (10 mg/kg), blood, liver, and kidney tissues were collected at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 12, 24, 36, 48, and 72 h (n = 6) for pharmacokinetic analysis. Muscle and oviduct tissues were additionally sampled at 1, 3, 7, 15, and 30 days post-dose (n = 6) for ENR content determination. Serum/tissue ENR concentrations were measured via Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) and analyzed using a non-compartmental model (WinNonLin 6.1 software) to calculate PK parameters including peak time (T_max), peak concentration (C_max), and area under the curve (AUC_0−t). In studying the physiology effects of ENR administration, biochemical enzyme activities and gene expressions in the liver and intestine were assessed post-ENR administration. Results: ENR demonstrated rapid absorption and extensive distribution in R. dybowskii. The withdrawal periods were determined to be over 33 days for females and 34 days for males in R. dybowskii. Following ENR administration, there was an increase in immune enzymes (AKP (alkaline phosphatase) and ACP (acid phosphatase)) as well as glycolytic enzymes (HK (hexokinase), PK (pyruvate kinase), PFK (phosphofructokinase)). Antioxidant enzyme levels, specifically SOD (superoxide dismutase) and CAT (catalase), peaked at 1.5 h post-ENR administration but subsequently declined by the 8 h mark. Additionally, following ENR treatment, IGF1, PI3K, and Akt exhibited up-regulation, whereas Keap1 and GYS1 showed down-regulation. Conclusions: The administration of ENR at a dosage of 10 mg/kg significantly enhances the activities of AKP and ACP, promotes glycolysis, and activates the Keap1/Nrf2 and PI3K-Akt signaling pathways in R. dybowskii. These findings establish a foundation for the rational application of ENR and the determination of withdrawal times in frog aquaculture. Full article

Objective: To investigate the effect of Lipopolysaccharide (LPS)-induced acute lung injury (ALI) on the pulmonary pharmacokinetics (PK) of a systemically administered antibody in mice. Method: The PK of a non-target-binding antibody was evaluated in healthy mice and mice with intratracheal instillation of 5 mg/kg LPS. The plasma, bronchoalveolar lavage (BAL), trachea, bronchi, and lung homogenate PK of the antibody were measured following intravenous administration of 5 mg/kg antibody dose. Noncompartmental analysis was performed to determine AUC values. Antibody concentrations in all biological matrices were quantified using qualified ELISA. The effect of ALI on BAL albumin and total protein concentrations was also determined. BAL protein concentrations were corrected for dilution using plasma urea concentrations. Results: Intratracheal instillation of LPS and the resultant ALI led to ~2–4-fold higher concentrations of albumin and proteins in the BAL. LPS-induced ALI also notably altered the pulmonary PK of the antibody. The effect of ALI on the antibody PK was time and tissue dependent. The trachea and bronchi showed ~1.7-fold and ~1.4-fold lower antibody exposure compared with the control group, but the BAL fluid exhibited ~4-fold increase in antibody exposure following LPS treatment. Most noticeable changes in antibody PK occurred 24 h after LPS administration, and the effect was temporary for the bronchi and trachea. However, the changes in lung homogenate and, more notably, in BAL persisted until the end of the experiment. Thus, our investigation suggests that due to the acute nature of ALI-induced pathophysiology and the changing severity of the disease, the dose and timing of antibody administration following ALI may need to be optimized based on the target site of action (e.g., bronchi, trachea, BAL, lung parenchyma, etc.) to maximize the therapeutic effect of the antibody. Conclusions: ALI may significantly affect pulmonary PK of systemically administered antibodies. Changes caused by ALI are time and tissue dependent, and hence, the timing and dose of antibody following ALI may need to be optimized to maximize the therapeutic effect of the antibody at the site of action. Full article

Objectives: There is growing concern over tyrosine kinase inhibitor (TKI)-induced cardiotoxicity, particularly regarding left ventricular dysfunction and heart failure in clinical treatment. These adverse effects often lead to treatment discontinuation, severely impacting patient outcomes. Therefore, there is an urgent need for more precise risk assessment methods. This study aimed to assess the cardiotoxicity of TKIs, refine in vitro to in vivo extrapolation (IVIVE) methodologies to improve predictive accuracy, and identify critical in vitro parameters for assessment. Methods: By leveraging high-throughput cardiotoxicity screening with human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), a mechanism-based toxicodynamic (TD) model for TKIs was constructed. A QSP-PK-TD model was developed by integrating pharmacokinetic (PK) and quantitative systems pharmacology (QSP) models. This model incorporates critical drug exposure factors, such as plasma protein binding, tissue–plasma partitioning, and drug distribution heterogeneity to enhance extrapolation accuracy. Results: The QSP-PK-TD model validated the reliability of IVIVE and identified the area under the curve of drug effects on mitochondrial membrane potential (AEMMP) and cardiomyocyte contractility (AEAAC) as key in vitro parameters for assessing TKI-induced cardiotoxicity. Incorporating critical drug exposure factors obviously improved qualitative and quantitative extrapolation accuracy. Conclusions: This study established a framework for predicting in vivo cardiotoxicity from in vitro parameters, enabling efficient translation of preclinical data into clinical risk assessment. These findings provide valuable insights for drug development and regulatory decision-making, offering a powerful tool for evaluating TKI-induced cardiotoxicity. Full article

Background/Objectives: Antibody–drug conjugates (ADCs) show significant promise in oncology but often suffer from a narrow therapeutic window. Introducing a positive charge on the antibody is one proposed strategy to enhance tumor distribution and efficacy of ADC. Accordingly, this study evaluates the pharmacokinetics (PK) and pharmacology of an ADC developed using a positively charged (+5) version of anti-HER2 antibody trastuzumab conjugated with vc-MMAE linker-payload. Methods: A positively charged variant of trastuzumab was generated and conjugated to vc-MMAE. In vitro cytotoxicity assays were performed in cell lines with varying HER2 expression levels: N87 (high), MCF-7 (low), and MDA-MB-468 (non-expressing). In vivo biodistribution of wild-type (WT) and positively charged (+5) ADC was investigated in plasma, tumors, liver, and spleen. A pilot efficacy and toxicity study was also conducted in N87 tumor-bearing mice. Results: The charged ADC showed differential potency and PK behavior compared to the WT ADC. The charged ADC had similar potency in N87 cells but demonstrated ~20-fold and ~60-fold higher potency in MCF-7 and MDA-MB-468 cells. Plasma exposures of all the analytes were found to be reduced following the administration of charged ADC. However, total antibody exposure was found to increase in liver, spleen, and low antigen-expressing MCF-7 tumors. Tumor payload exposures were found to be significantly reduced for the charged ADCs, but liver and spleen displayed higher peak concentrations and increased tissue-to-plasma exposure ratios for the payload, suggesting preferential distribution of ADC with high drug–antibody ratio (DAR) to liver and spleen. Consistent with reduced tumor exposures, charged ADC showed lower efficacy in N87 tumor-bearing mice. No overt toxicity was observed for the charged ADC. Conclusions: Our findings suggest that while positively charged ADCs may be more potent in vitro, their efficacy in vivo may be compromised due to altered PK behavior. Thus, introducing a positive charge into the antibody framework may not be a viable strategy for improving the therapeutic potential of ADCs. Full article

Objectives: To investigate the pharmacokinetics (PK) of the monoclonal antibody (mAb) in male reproductive tissues and develop a translational physiologically based pharmacokinetic (PBPK) model to characterize the PK data. Method: The PK of a non-cross-reactive antibody (trastuzumab) was investigated in human FcRn-expressing male mice following a 10 mg/kg intravenous dose. The PK in plasma and male reproductive tissues (i.e., epididymis, testes, vas deferens, seminal vesicles, and prostate glands) were evaluated. The observed PK data in mice were mathematically characterized using a novel PBPK model for antibodies that contained male reproductive systems. The mouse PBPK model was scaled to rats, monkeys, and humans to predict the PK of antibodies in male reproductive organs across animal species. Results: Plasma and tissue PK data generated in mice suggest that antibody distribution in male reproductive tissues is generally lower compared to that of most of the organs. The antibody exposure in the testes was 1.70%, in the epididymis was 2.57%, in the vas deferens was 2.01%, in the seminal vesicle was 0.42%, and in the prostate gland was 0.52% of the plasma exposure. The plasma and tissue PK data were simultaneously characterized using the PBPK model, which incorporated the novel male reproductive system. All the predicted PK profiles were within two-fold of the observed data, as indicated by percentage prediction error (%PE) values. The mouse model was successfully translated to bigger animals, and the model was used to simulate the PK of antibodies in rat, monkey, and human male reproductive systems. Conclusions: The combination of the experimental data and novel PBPK model presented here provides unprecedented insights into the antibody distributions in different male reproductive tissues. The PBPK model can serve as a crucial tool for advancing the development of antibody-based therapies for treating sexually transmitted infections (STIs), cancers, and contraceptives. Full article

Background/Objectives: N-acetyl-galactosamine small interfering RNAs (GalNAc-siRNA) are an emerging class of drugs due to their durable knockdown of disease-related proteins. Direct conjugation of GalNAc onto the siRNA enables targeted uptake into hepatocytes via GalNAc recognition of the Asialoglycoprotein Receptor (ASGPR). With a transient plasma exposure combined with a prolonged liver half-life, GalNAc-siRNA exhibits distinct disposition characteristics. We aimed to develop a generic GalNAc-siRNAs whole-body physiologically based pharmacokinetic–pharmacodynamic (WB-PBPK-PD) model for describing the pharmacokinetic–pharmacodynamic (PK-PD) relationship and overall tissue distribution in the open-source platform Open Systems Pharmacology Suite. Methods: Model development was performed using published studies in mice leveraging the PK-Sim^® standard implementation for large molecules with added implementations of ASGPR-mediated liver disposition and downstream target effects. Adequate model performance was achieved across study measurements and included studies adopting a combination of global and compound-specific parameters. Results: The analysis identified significant compound dependencies, e.g., endosomal stability, with direct consequences for the pharmacological effect. Additionally, knowledge gaps in mechanistic understanding related to extravasation and overall tissue distribution were identified during model development. The presented study provides a generic WB-PBPK-PD model for the investigation of GalNAc-siRNAs implemented in a standardized open-source platform. Full article

Background/Objectives: Colorectal cancer (CRC) holds the third and second position among cancers affecting men and women, respectively. Frequently, the first-line treatment for metastatic CRC consists of the intravenous administration of 5-fluorouracil and leucovorin in combination with oxaliplatin or irinotecan. Physiologically-based pharmacokinetic models (PBPK) aim to mechanistically incorporate body physiology and drug physicochemical attributes, enabling the description of both systemic and organ drug exposure based on the treatment specificities. This bottom-up approach represents an opportunity to personalize treatment and minimize the therapeutic risk/benefit ratio through the understanding of drug distribution within colorectal tissue. This project has the goal of characterizing the systemic and tissue exposure of four anti-cancer drugs in humans using a PBPK platform fed with data from the literature. Methods: A literature search was performed to collect clinical data on systemic concentration versus time profiles. Physicochemical features were obtained from the literature, as well as parameters associated with distribution, metabolism, and excretion. The PBPK models were built using PK-Sim^®. Results: The data from 51 clinical studies were extracted and combined in one single dataset. The PBPK models successfully described the exposure vs. time profiles with respect to both, with both the typical tendency and dispersion shown by the data. The percentage of observations falling within the two-fold error bounds ranged between 94 and 100%. The colon/plasma AUC_inf ratios were similar for 5-FU, oxaliplatin, and leucovorin, but it was significantly higher for irinotecan. Conclusions: The PBPK models support tailored treatment approaches by linking in vitro studies to organ exposure. These models serve as the initial step towards incorporating a dedicated tumor compartment, which will further account for the variability in tumor microenvironment characteristics to improve therapeutic strategies. Full article

Background/Objectives: Paclitaxel (PTX), a commonly used chemotherapy for breast cancer (BC), is associated with dose-limiting toxicities (DLTs) such as peripheral neuropathy and neutropenia. These toxicities frequently lead to dose reductions, treatment delays, or therapy discontinuation, negatively affecting patients’ quality of life and clinical outcomes. Current dosing strategies based on body surface area (BSA) fail to account for individual variations in body composition (skeletal muscle mass (SMM) and adipose tissue (AT) mass) and physical activity (PA), which can influence drug metabolism and toxicity. This study aims to explore the relationships between PTX pharmacokinetics, body composition, and PA to predict DLTs. Methods: This single-group observational cohort study will recruit 40 female BC patients undergoing PTX treatment. Data collection will include plasma PTX concentrations, body composition assessments (using dual X-ray absorptiometry and bioelectrical impedance analysis), PA measurements (via accelerometers), and questionnaires to assess BC-related health-related quality of life, chemotherapy-induced peripheral neuropathy, and neutropenia during the PTX schedule using validated questionnaires. Dose-limiting toxicities will be graded according to the Common Terminology Criteria for Adverse Events v5.0 (grade 3 or higher). This protocol is designed to develop a population-based PK-PD model that predicts the occurrence of chemotherapy-induced peripheral neuropathy and neutropenia in women with stage II or III BC undergoing PTX therapy, focusing on explanatory outcomes related to SMM, AT mass, and PA. Full article

Background: Glioblastoma is an aggressive and incurable type of brain cancer. Little progress has been made in the development of effective new therapies in the past decades. The blood–brain barrier (BBB) and drug efflux pumps, which together hamper drug delivery to these tumors, play a pivotal role in the gap between promising preclinical findings and failure in clinical trials. Therefore, selecting drugs that can reach the tumor region in pharmacologically effective concentrations is of major importance. Methods: In the current study, we utilized a drug selection platform to identify candidate drugs by combining in vitro oncological drug screening data and pharmacokinetic (PK) profiles for central nervous system (CNS) penetration using the multiparameter optimization (MPO) score. Furthermore, we developed intracranial patient-derived xenograft (PDX) models that recapitulated the in situ characteristics of glioblastoma and characterized them in terms of vascular integrity, BBB permeability and expression of ATP-binding cassette (ABC) transporters. Omacetaxine mepesuccinate (OMA) was selected as a proof-of-concept drug candidate to validate our drug selection pipeline. Results: We assessed OMA’s PK profile in three different orthotopic mouse PDX models and found that OMA reaches the brain tumor tissue at concentrations ranging from 2- to 11-fold higher than in vitro IC₅₀ values on patient-derived glioblastoma cell cultures. Conclusions: This study demonstrates that OMA, a drug selected for its in vitro anti-glioma activity and CNS- MPO score, achieves brain tumor tissue concentrations exceeding its in vitro IC₅₀ values in patient-derived glioblastoma cell cultures, as shown in three orthotopic mouse PDX models. We emphasize the importance of such approaches at the preclinical level, highlighting both their significance and limitations in identifying compounds with potential clinical implementation in glioblastoma. Full article

Autoimmune diseases (AIDs) are a group of disorders in which the immune system attacks the body’s own tissues, leading to chronic inflammation and organ damage. These diseases are difficult to treat due to variability in drug PK among individuals, patient responses to treatment, and the side effects of long-term immunosuppressive therapies. In recent years, pharmacometrics has emerged as a critical tool in drug discovery and development (DDD) and precision medicine. The aim of this review is to explore the diverse roles that pharmacometrics has played in addressing the challenges associated with DDD and personalized therapies in the treatment of AIDs. Methods: This review synthesizes research from the past two decades on pharmacometric methodologies, including Physiologically Based Pharmacokinetic (PBPK) modeling, Pharmacokinetic/Pharmacodynamic (PK/PD) modeling, disease progression (DisP) modeling, population modeling, model-based meta-analysis (MBMA), and Quantitative Systems Pharmacology (QSP). The incorporation of artificial intelligence (AI) and machine learning (ML) into pharmacometrics is also discussed. Results: Pharmacometrics has demonstrated significant potential in optimizing dosing regimens, improving drug safety, and predicting patient-specific responses in AIDs. PBPK and PK/PD models have been instrumental in personalizing treatments, while DisP and QSP models provide insights into disease evolution and pathophysiological mechanisms in AIDs. AI/ML implementation has further enhanced the precision of these models. Conclusions: Pharmacometrics plays a crucial role in bridging pre-clinical findings and clinical applications, driving more personalized and effective treatments for AIDs. Its integration into DDD and translational science, in combination with AI and ML algorithms, holds promise for advancing therapeutic strategies and improving autoimmune patients’ outcomes. Full article

P. aeruginosa biofilms are aggregates of bacteria surrounded by a self-produced matrix which binds to some antibiotics such as aminoglycosides. P. aeruginosa biofilms are tolerant to antibiotics. The treatment of biofilm infections leads to a recurrence of symptoms after finishing antibiotic treatment, although the initial clinical response to the treatment is frequently favorable. There is a concentration gradient of oxygen and nutrients from the surface to the center of biofilms. Surface-located bacteria are multiplying and metabolizing, whereas deeper located bacteria are dormant and tolerant to most antibiotics. Colistin kills dormant bacteria, and combination therapy with colistin and antibiotics which kills multiplying bacteria is efficient in vitro. Some antibiotics such as imipenem induce additional production of the biofilm matrix and of chromosomal beta-lactamase in biofilms. Biofilms present a third Pharmacokinetic/Pharmacodynamic (PK/PD) micro-compartment (first: blood, second: tissue, third: biofilm) which must be taken into consideration when calculations try to predict the antibiotic concentrations in biofilms and thereby the probability of target attainment (PTA) for killing the biofilm. Treating biofilms with hyperbaric oxygen to wake up the dormant cells, destruction of the biofilm matrix, and the use of bacteriophage therapy in combination with antibiotics are promising possibilities which have shown proof of concept in in vitro experiments and in animal experiments. Full article