JournalTOCs

AAPS Journal
Journal Prestige (SJR): 1.118

Citation Impact (citeScore): 4
Number of Followers: 29

Hybrid journal (It can contain Open Access articles)
ISSN (Online) 1550-7416
Published by Springer-Verlag

[2468 journals]

Physiologically Based Modeling of Cefoxitin, Cefazolin, and Piperacillin
Pharmacokinetics in Obese and Lean Rats
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  Abstract: The prevalence of obesity is rapidly increasing worldwide, however there is a notable gap in understanding how obesity affects the pharmacokinetics of drugs and how dosing should be adjusted in obese population. The goals of this work were to evaluate plasma pharmacokinetics and tissue disposition of piperacillin, cefazolin, and cefoxitin in a rat model of diet-induced obesity compared to a lean cohort. Male Long-Evans rats were fed high-fat or control diets for 23 weeks. Various measures of body size and composition were collected. The animals were administered a mixture containing 50 mg/kg cefoxitin, 50 mg/kg cefazolin, and 120 mg/kg piperacillin. Plasma and tissues were collected and analyzed using a validated LC-MS/MS method. Whole-body physiologically-based pharmacokinetic (PBPK) models were develop to capture the biodistribution of these drugs in lean and obese cohorts. Most plasma and tissue concentrations were comparable between lean and obese rats after dosing based on mg/kg of total body weight; however, in some tissues concentration was consistently higher in obese animals. PBPKs successfully captured biodistribution of three drugs and both cohorts; however, cohort-specific (lean or obese) parameters were required for liver (for cefoxitin and cefazolin) and spleen (for all three drugs) for capturing the data.The results support the necessity of using mg/kg dosing for obese rats to achieve drug exposure comparable to that of lean rats. In the future, these models could be extended to predict plasma pharmacokinetics and tissue disposition of cefoxitin, cefazolin, and piperacillin in humans by incorporating interspecies scaling approaches. Graphical Abstract
  PubDate: 2025-04-17
Assessing the Impact of Multiple Imputation Algorithms on Pharmacokinetic
Model Performance: A Simulation-Based Study
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  Abstract: This study compared multiple imputation (MI) algorithms in a one-compartment pharmacokinetic (PK) scenario with oral absorption. Four covariates (two continuous, two dichotomous) linked to PK parameters were randomly removed under a missing completely at random (MCAR) mechanism. The aim was to identify which algorithm best preserves covariate distributions and PK parameter estimates. The original dataset included 100 individuals, each with five sampling occasions. Missing data were introduced at 5%, 20%, 50%, and 75% for the four covariates under the MCAR assumption. Five MI algorithms (Mice, Amelia, missForest, rMIDAS, XGBoost) were tested. Absolute and relative errors and concordance metrics were used to assess performance. Population and individual parameter estimates were compared across imputed and original datasets using Monolix2024R1®. MissForest (MF) and Amelia yielded lower errors for continuous covariates whereas dichotomous variables were poorly imputed. Based on objective function values, Mice perform best at 5% and MF at 20% of missingness. Increasing missingness decreased covariate effects and increased the estimated inter-individual variances. Individual parameter estimation accurately captured individual-level variability across all imputed datasets. MI methods appear effective for covariate imputation in PK modeling, offering reliable results up to 20% missingness under an MCAR mechanism. Future research should explore refined strategies, including advanced modeling frameworks and Bayesian approaches for imputation. Enhancing our understanding of missing data processes will be crucial for robust PK analyses across diverse clinical settings. Graphical Abstract
  PubDate: 2025-04-17
A Tool to Eliminate IgM Immunoassay Interference
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  Abstract: IgM-selective proteolytic cleavage can become a groundbreaking tool for immunoassay-based bioanalysis. We tested the utility of a newly introduced IgM-selective protease in three different bioanalytical applications and showed that protease treatment can eliminate rheumatoid factor interference and simplify IgM isotyping. Surprisingly, we discovered that a gene therapy-induced immune response was underestimated in an anti-capsid IgG assay when treatment-emergent IgM were present in the matrix. Selective IgM digestion eliminated this interference. Graphical Abstract
  PubDate: 2025-04-11
Application of DOE to ELISA Robustness and Ruggedness Assessment
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  Abstract: Complex assays such as immunoassays can be affected by robustness and ruggedness factors. Associated risks can be reduced by a systematic performance assessment across key factors followed by control strategies. However, the large number of factors and their interactions can represent an experimental challenge. Statistical Design of Experiments (DOE) allows efficient evaluation of more factors with fewer total assay runs in addition to assessing potential factor interactions. We applied DOEs to the robustness evaluation of a vaccine potency ELISA. Test factors were selected based on a review and ranking of development data, scientific experience, and commonly expected sources of variability. Comparing different design options with 16–20 runs which was a laboratory limit, a 16-run Resolution III design was selected based on the total number of runs, the degree of factor confounding, and the potential projection properties. DOE data were first visually analyzed by plotting the concentration-responses of reference curves against DOE Runs followed by detailed statistical models of the maximum fluorescent curve signal and the WRMSE fit values. Initial confounding between factors and their interactions was reduced by eliminating factors with no impact from the models and by removing factors or interactions based on their likelihood of an impact after applying statistical and scientific expertise. Despite initial confounding, the designs allowed discerning an impact of plate manufacturer with interaction of coating concentration and time out of 15 factors with only 16 runs. Graphical Abstract
  PubDate: 2025-04-03
GCN-BBB: Deep Learning Blood-Brain Barrier (BBB) Permeability
PharmacoAnalytics with Graph Convolutional Neural (GCN) Network
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  Abstract: The Blood-Brain Barrier (BBB) is a selective barrier between the Central Nervous System (CNS) and the peripheral system, regulating the distribution of molecules. BBB permeability has been crucial in CNS-targeting drug development, such as glioblastoma-related drug discovery. In addition, more CNS diseases still present significant challenges, for instance, neurological disorders like Alzheimer’s Disease (AD) and drug abuse. Conversely, cannabinoid drugs that do not cross the BBB are needed to avoid off-target CNS psychotropic effects. In vitro and in vivo experiments measuring BBB permeability are costly and low throughput. Computational pharmacoanalytics modeling, particularly using deep-learning Graph Neural Networks (GNNs), offers a promising alternative. GNNs excel at capturing intricate relationships in graph-based information, such as small molecular structures. In this study, we developed GNNs model for BBB permeability using the graph representation of drugs. The GNNs were compared with other algorithms using molecular fingerprints or physical–chemical descriptors. With a dataset of 1924 molecules, the best GNNs model, a convolutional graph neural network using a normalized Laplacian matrix (GCN_2), achieved a precision of 0.94, recall of 0.96, F1 score of 0.95, and MCC score of 0.77. This outperformed other machine learning algorithms with molecular fingerprints. The findings indicate that the graphic representation of small molecules combined with GNNs architecture is powerful in predicting BBB permeability with high accuracy and recall. The developed GNNs model can be utilized in the initial screening stage for new drug development. Graphical Abstract
  PubDate: 2025-04-03
Survey and Establishment of Points to Consider for Application of
Analytical Techniques to Evaluate Protein Aggregates and Insoluble
Particles in Biopharmaceuticals: Experiences in Japan Biopharmaceutical
Consortium
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  Abstract: Protein aggregates and insoluble particles in biopharmaceutical products are impurities that can elicit immunogenicity. The protein aggregates and insoluble particles form during manufacturing and storage, and should be characterized to optimize the manufacturing process and establish a control strategy. Several issues regarding the evaluation and control of these particles have been concerned, and collaborative studies have been conducted in the Japan Biopharmaceutical Consortium to address them. However, there is still no consensus for utilizing analytical techniques in parallel to establish a control strategy for such protein aggregates and insoluble particles, which range in size from a few nanometers to several hundred micrometers. Therefore, in this study, we surveyed Japanese biopharmaceutical companies through a questionnaire including questions regarding analytical techniques used to establish control strategies for protein aggregates and insoluble particles at various development phases. To summary the survey results, we found that size exclusion chromatography, light obscuration, and visual inspection are consistently used from early development and formulation optimization stage to commercial manufacturing. Apart from the light obscuration method, flow imaging (FI) was the most commonly used technique for subvisible particle characterization; thus, the use of FI to establish a control strategy was documented. The recommendation for establishing a control strategy for protein aggregates and insoluble particles based on life-cycle of drug development are summarized.
  PubDate: 2025-04-03
Effect of FcRn Binding on Monoclonal Antibody Disposition in the Brain
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  Abstract: This study investigates the role of FcRn in brain disposition of monoclonal antibodies. Human FcRn (hFcRn) expressing mice and different FcRn binding variants of a non-target binding antibody trastuzumab (WT) were used for the investigation. The FcRn binding mutations were: YTE, YPY, YQAY, and IHH. YQAY and YPY mutants have enhanced FcRn binding at both neutral and acidic pH (7+/6+). YTE mutant has enhanced FcRn binding at only acidic pH (7-/6+), and IHH mutant has no FcRn binding (7-/6-). The pharmacokinetics (PK) of these mutants in plasma, brain interstitial fluid (ISF), and brain homogenate were measured following intravenous administration. The area under the concentration-time curve (AUC) for all PK profiles and ratios of brain and plasma AUCs were calculated for comparison. Results showed that WT antibody had brain:plasma AUC ratio of 0.70% and ISF:plasma AUC ratio of 0.59%. Among all mutants, YPY exhibited the highest AUC ratio for brain (3.86%) and ISF (3.49%). YQAY had relatively high AUC ratios of 1.49% in the brain and 0.81% in ISF. YTE showed a similar AUC ratio in the brain (0.60%) and ISF (0.62%) compared to WT, while IHH exhibited similar AUC ratio in the brain (0.52%) but higher AUC ratio in ISF (2.48%). The results suggest that binding to FcRn at neutral and acidic pH facilitates transcytosis of antibody into the brain. Just increasing the binding to FcRn at acidic pH does not impact the disposition of antibody in the brain. Complete removal of FcRn binding might lead to prolonged retention of antibody in ISF. Together, these data demonstrate that FcRn significantly affects brain disposition of antibody, and engineering of Fc domain to alter the binding of antibody to FcRn may be exploited to achieve better exposure of antibodies in the brain. Graphical Abstract
  PubDate: 2025-04-01
Virtual Bioequivalence Assessment of Tofacitinib Once Daily Modified
Release Dosage Form in Pediatric Subjects
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  Abstract: Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family of kinases with a high degree of selectivity within the human genome’s set of protein kinases. Currently approved formulations for tofacitinib citrate are immediate release (IR) tablets, modified release (MR) tablets and IR solution. A once daily MR microsphere formulation was developed for pediatric patients. Previously, bioequivalence (BE) between the 10 mg once daily (QD) MR microsphere formulation and 5 mg twice daily (BID) IR solution has been established with PBPK virtual BE trials (VBE) in place of a clinical BE trial in healthy adult population. In this research, the PBPK model based VBE approach was extended to pediatric population. Pediatric PBPK model verification was conducted by first examining predicted vs observed demographic information such as body weight (BWT) and glomerular filtration rate (GFR). After confirming the alignment in demographic background between clinical study participants vs virtual pediatric subjects, multiple ontogeny profiles for CYP3A4 and CYP2C19 were examined. The established model predicted AUC and Cmax within 1.5-fold of observed values for multiple trials, age groups and formulations. Lastly, VBE trials in pediatric subjects were conducted with PBPK model generated pharmacokinetic (PK) parameter values with clinically observed intra-subject coefficient of variation (ICV) in adults. Since ICV in pediatric population is unknown, the sensitivity around ICV was also evaluated to assess the BE risk between IR solution and MR microsphere formulation in pediatric population. The results demonstrated that the IR oral solution BID and MR microsphere formulation QD are BE in pediatric population.
  PubDate: 2025-04-01
The Drug Titration Paradox in the Presence of Intra-Individual Variation:
Can we Estimate the True Concentration-Effect Relationship'
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  Abstract: The drug titration paradox arises when higher drug concentrations are paradoxically associated with poorer efficacy outcomes, due to the titration of an individual’s drug dose to achieve a desired effect. In cases with substantial intraindividual variability of the disease state, the drug titration paradox can also occur on the individual level (resulting in a higher dose when the individual has a worse disease state) and it has been suggested that it may not be possible to estimate the true exposure–response (ER) relationship in such situations. We simulated a titration study with strong intra-individual variability of disease state (causing the drug titration paradox at the individual level) and investigated the performance of four PKPD modelling methods in obtaining an unbiased estimate of the ER relationship. Strong bias in the estimated ER relationship was observed with two commonly used modelling methods: the model which only estimated inter-individual variability (IIV) and the model that included IIV and inter-occasion variability (IOV) on disease severity. In contrast, inclusion of stochastic differential equations (SDE) or accounting for the autocorrelation of the residual error between observations did yield successful estimation of the ER relationship without bias. The success of these methods can be understood from the principles of causal inference: confounding is avoided by controlling for the previous observations which drive the drug titration. Our results underline the importance of adequately characterizing intra-individual variability to avoid bias in PKPD modelling, especially for clinical areas where titration designs are common, such as analgesia. Graphical Abstract
  PubDate: 2025-03-26
Nomlabofusp, a Fusion Protein of Human Frataxin and a Cell Penetrant
Peptide, Delivers Mature and Functional Frataxin into Mitochondria
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  Abstract: Friedreich’s ataxia is a rare, progressive, genetic disorder, the root cause of which is a significant deficiency in the mitochondrial protein frataxin. Frataxin is ubiquitously expressed, but its deficiency results in a variety of debilitating symptoms, with disease severity, rate of progression and age of onset inversely correlating with tissue frataxin levels. Nomlabofusp is a novel cell penetrant peptide based recombinant fusion protein designed to enter cells and deliver human FXN into the mitochondria. Using immunofluorescence staining and western blot we show that frataxin delivered by nomlabofusp is detected in the mitochondria of H9c2 and SH-SY5Y cells. Also in these cells, and in C2C12 and HEK293 cells, we demonstrate the presence of mature frataxin after nomlabofusp exposure. Finally, using buccal swab tissue samples taken from study subjects in a Phase 1 clinical trial who received nomlabofusp, we show increases in mature frataxin levels along with marked changes in gene expression post-administration suggesting intracellular pharmacodynamic activity. Together, these results demonstrate that nomlabofusp enters the cell and localizes to the mitochondria, releasing mature frataxin that appears to be biologically active and support the use of nomlabofusp as a potential treatment for patients with Friedreich’s ataxia. Graphical Abstract
  PubDate: 2025-03-26
Establishing a Platform Method for Physical Appearance Assessment of New
Parenteral Pharmaceuticals
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  Abstract: Physical appearance (PA) is an attribute indicating the quality of parenteral pharmaceuticals. It is routinely evaluated during release and stability testing and included in regulatory filings. PA assessment of liquids involves three tests: visible particulates, clarity, and color. For each test, compendial general method chapters are available requiring minimal modification. This allows for a platform PA method approach, streamlining method readiness for new test articles. However, selecting the appropriate method is challenging, as no method suits all test articles, and pharmacopeias do not specify suitable condition(s) for each method. Improper method selection can lead to inappropriate specification setting and unreliable results. The need for guidance is especially urgent for vaccines, which often exhibit a wide range of PA attributes due to complex delivery systems and adjuvants that boost immunogenicity. This manuscript addresses this challenge by explaining method suitability and presenting a decision table for PA method selection based on the appearance properties of pharmaceuticals. A case study involving a yellow-turbid vaccine adjuvant is presented to demonstrate the practical application of the decision table. When color and turbidity make visual comparison to reference liquids difficult, instrumental clarity and visual qualitative methods are suitable options. The manuscript provides valuable insights on PA method selection and setting specifications for new parenteral pharmaceuticals. Furthermore, the decision table enables platform methods for test articles sharing similar appearance properties, eliminating the need for individual methods, reducing document preparation time for method and verification protocol, and enhancing the consistency and efficiency of GMP testing for PA. Graphical Abstract
  PubDate: 2025-03-26
Leveraging Buprenorphine and Halofantrine as Tool Molecules to Develop a
Novel Semi-Physiologically based Pharmacokinetic Model Accounting for
Gastro-Intestinal Lymphatic Absorption and Enabling Cross-Species
Translation
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  Abstract: Intestinal lymphatic absorption is a crucial alternative to portal uptake for highly lipophilic drugs (log P > 5), bypassing first-pass metabolism. Unlike the portal-hepatic pathway, lymphatic uptake is rarely considered in physiologically based pharmacokinetic (PBPK) models for oral delivery. Our study developed an innovative Gastro-Intestinal (GI)-lymph-PBPK model that includes GI absorption, chylomicron extraction (CE) to rescue drugs from gut extraction (GE), and bypass hepatic extraction (HE). This model introduces CE clearance (CLCE), competing with GE clearance, to estimate the drug proportion subjected to CE versus GE. PBPK analysis for Buprenorphine revealed extensive GE (0.87) and HE (0.58), explaining the low bioavailability (F%) of 5.28% in rats. Buprenorphine prodrugs activated CLCE, leading to CE ranging from 0.37 to 0.79, boosting oral F% to 39.9%-79.9% in rats. To translate from rat to human, our model considered species differences in GI transit time, formulation, food-dependent drug dissolution, allometric scaling in CLCE, and between species variability in gut metabolism. Using Halofantrine, we established an allometric scaling factor for CLCE at 1.1. Accounting for six times faster human gut metabolism, our model predicted an extremely low oral F% of 0.382% for Buprenorphine in humans. Incorporating the allometric scaled CLCE competing with the extensive gut metabolism, our model predicted Buprenorphine prodrugs remains effective in enabling substantial absorption boosts, with oral F% estimates ranging from 15.8% to 56.7% in humans. This study highlights the significant potential of GI-lymph-PBPK modeling in predicting intestinal lymphatic absorption and facilitating cross-species translation. Graphical Abstract
  PubDate: 2025-03-26
Lipid Nanoparticles for mRNA Delivery in Cancer Immunotherapy
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  Abstract: Cancer immunotherapy is poised to be one of the major modalities for cancer treatment. Messenger RNA (mRNA) has emerged as a versatile and promising platform for the development of effective cancer immunotherapy. Delivery systems for mRNA therapeutics are pivotal for their optimal therapeutic efficacy and minimal adverse side effects. Lipid nanoparticles (LNPs) have demonstrated a great success for mRNA delivery. Numerous LNPs have been designed and optimized to enhance mRNA stability, facilitate transfection, and ensure intracellular delivery for subsequent processing. Nevertheless, challenges remain to, for example, improve the efficiency of endosomal escape and passive targeting. This review highlights key advancements in the development of mRNA LNPs for cancer immunotherapy. We delve into the design of LNPs for mRNA delivery, encompassing the chemical structures, characterization, and structure–activity relationships (SAR) of LNP compositions. We discuss the key factors influencing the transfection efficiency, passive targeting, and tropism of mRNA-loaded LNPs. We also review the preclinical and clinical applications of mRNA LNPs in cancer immunotherapy. This review can enhance our understanding in the design and application of LNPs for mRNA delivery in cancer immunotherapy.
  PubDate: 2025-03-18
Enhancing Efavirenz Bioavailability Via Polymer-Based Buccal
Administration: Optimization and Characterization of Nanocrystal-Loaded
Dissolving Microneedle Delivery Systems
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  Abstract: Efavirenz (EFV) is a widely utilized antiretroviral agent in HIV/AIDS therapy that is known for its efficacy but is also associated with various side effects. For improved drug delivery, buccal administration offers a promising alternative by allowing the drug to enter the systemic circulation directly through the oral mucosa, bypassing the gastrointestinal tract and first-pass metabolism. This study explored the interaction between EFV and different polymers through molecular docking, revealing a strong binding affinity to Pluronic®F-127 (-2.1 kcal/mol). EFV was formulated into nanocrystals (EFV-NC) using Pluronic®F-127 as the stabilizer, characterized by an average particle size of 174.83 ± 15.21 nm, a narrow size distribution (PDI of 0.15 ± 0.013), and good stability (zeta potential of -22.27 ± 1.12 mV). FTIR and XRD analyses revealed polymer-induced alterations in the crystalline structure of the EFV. The EFV-NC formulation enhanced the solubility (up to 400 µg/mL) and achieved 89.58 ± 4.01% drug release within 24 h, following the Higuchi model kinetics for controlled release. EFV-NC-loaded dissolving microneedles (EFV-NC-DMN) demonstrated robust mechanical properties, efficient tissue penetration, and minimal moisture absorption. Ex vivo and in vivo studies revealed that compared with oral EFV, EFV-NC-DMN provided a relative bioavailability of 137.40%, with higher plasma concentrations and prolonged release, highlighting its potential for superior HIV/AIDS management via buccal administration and improved therapeutic outcomes. Graphical Abstract
  PubDate: 2025-03-14
Therapeutic Drug Monitoring of Biologics: Current Practice, Challenges and
Opportunities – a Workshop Report
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  Abstract: Therapeutic drug monitoring (TDM) for dose modification of biologics has the potential to improve patient outcomes. The US Food and Drug Administration (FDA) and the American Association of Pharmaceutical Scientists (AAPS) hosted the first US-based public workshop on TDM of biologics with contributions from a broad array of interested parties including healthcare providers, clinical pharmacologists, test developers, bioanalysis and immunogenicity scientists, health economics and outcomes research (HEOR) experts and regulators. The key insight was that despite a body of evidence to support TDM in certain therapeutic areas, there remain substantial challenges to widespread clinical implementation. There is a lack of consensus regarding the integration of TDM in clinical guidelines, and a lack of consensus on the cost-effectiveness of TDM; both factors contribute to the difficulty that healthcare providers face in obtaining reimbursement for TDM (both coverage of testing itself, and coverage of potential dosing modifications). The HEOR experts outlined alternative routes to obtaining reimbursement and suggested advocating for changes in coverage policies to promote TDM use in the clinic. Reaching alignment across policy makers, patients and advocacy groups, payers, and healthcare providers, on specific treatment settings where TDM will be clearly beneficial, was identified as an important step to advancing TDM implementation for the benefit of patients. Graphical abstract
  PubDate: 2025-03-14
Characterizing the Hepatic Metabolic Pathway of Ketone Ester and
Subsequent Metabolites Using Human and Rat Liver Fractions
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  Abstract: Although exogenous ketogenic dietary supplements continue to grow in popularity, their pharmacokinetic properties have not been adequately studied, thus hindering their optimal use and benefits. Here, the metabolic characteristics of one such supplement (Veech ketone mono-ester ((R)-3-hydroxybutyl(R)-3-hydroxybutyrate) (KE)) were studied along with its metabolite- (R)-1,3-butanediol ((R)-1,3-BD), both of which are precursors and undergo metabolic conversion to (R)-beta-hydroxybutyrate (BHB). The metabolism of aldol (an aldehyde intermediate between the conversion of (R)-1,3-BD to (R)-BHB was also evaluated, as it is frequently not considered in any scientific discussion. The metabolic parameters were calculated using pooled human (mixed gender) and pooled rat (male and female) liver fractions. These were later used to estimate the hepatic extraction ratio and the hepatic clearance of these molecules. KE showed rapid and non-saturable clearance in human and rat liver fractions, even at concentrations as high as 15,000 μM. In the case of (R)-1,3-BD, there was saturable metabolism in rats and humans with Km and Vmax values of 8,000 μM and 27.1 nmol/min/mg of protein (humans), 19,300 μM and 113.5 nmol/min/mg of protein (male rats), and 11,910 μM and 75.8 nmol/min/mg of protein (female rats). The metabolism of aldol showed rapid and non-saturable hepatic clearance in human liver fractions.
  PubDate: 2025-03-14
The Role of Enhanced Analytical Procedure Development in Facilitating
Post-Approval Changes Via Established Conditions
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  Abstract: Enabling greater flexibility for lifecycle management of analytical procedures is one of the primary features of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q12 Lifecycle Management guideline. Rather than rely on a comparatively slower and burdensome post-approval change supplement process, ICH Q12 created a new pathway to facilitate changes to chemistry, manufacturing, and controls. The new framework utilized key concepts such as established conditions (ECs), post-approval change management protocols, and the product lifecycle management document to allow modifications to analytical procedures based upon pre-approved conditions. Shortly after the publication of ICH Q12, the ICH Q14 Analytical Procedure Development guideline provided further guidance on how knowledge gained during analytical procedure development could be incorporated with the ICH Q12 framework to support scientifically sound and risk-based post-approval changes. However, to date, the full potential of ICH Q12 and Q14 remains unrealized, likely due to uncertainty over how analytical procedure development data can be effectively utilized to gain regulatory flexibility for post-approval changes. In this case study, an example of determining, proposing, and justifying analytical procedure ECs, reporting categories, and identification of elements not considered ECs is presented. In addition, how such information could be presented in a regulatory submission is described. Importantly, this case study serves as an example of the application of ICH Q12 and Q14 principles for analytical procedures, but it is not intended to serve as official guidance nor to define the full scope of information required in a regulatory submission. Graphical Abstract
  PubDate: 2025-03-14
A Facile Way to Enhance the Therapeutic Efficacy of Hydrophobic Drugs via
Amorphous Solid Dispersions
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  Abstract: Approximately 40% of marketed drugs and 75% of invested drugs in the pharmaceutical field are poorly soluble hydrophobic drugs with minimal solubility in water which make them difficult to be absorbed by the body and significantly limiting their applications. Among chemotherapeutic agents, numerous antitumor drugs such as platinum compounds, camptothecin, paclitaxel and others are also restricted in processing and preparation due to solubility issues. Therefore, improving the solubility and enhancing the therapeutic efficacy of drugs have always been significant research topics in current pharmaceutics. Herein, we propose an amorphous solid dispersion system PRTA-DOX, involving the protein drug protamine sulphate and hydrophobic doxorubicin as the model hydrophobic drug. In previous studies, ASD (Amorphous Solid Dispersion) has been demonstrated to enhance the solubility of hydrophobic drugs and result in a storage-stable system. Protamine sulphate as a marketed drug is reliable in safety and conveniently obtained. Doxorubicin, an antitumor drug with a broad antitumor spectrum, is commonly used in the treatment of breast cancer. Typically, doxorubicin is prepared in the form of a hydrochloride salt to increase its solubility. However, the utilization of doxorubicin hydrochloride is reduced due to drug resistance issues in biological cells and it exhibits higher toxicity to the body. In this system, protamine sulphate which is rich in arginine guanidino hydrophobic planes physically mixes with doxorubicin which is a hydrophobic molecule with aromatic rings and they are connected through weak interactions: π-π conjugation. They constitute an amorphous solid dispersion system which increases the solubility of hydrophobic doxorubicin, enhances cellular uptake, mitigate some cellular drug resistance and thereby achieves the purpose of improving therapeutic efficacy.
  PubDate: 2025-03-14
PBPK Modeling to Recommend Nevirapine Dosing in HIV and HIV-TB Co-infected
Patients: Leveraging Enzyme Auto-Induction, Drug Interactions, and Ethnic
Variability
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  Abstract: Nevirapine, primarily metabolized by CYP2B6 and CYP3A4, exhibits enzyme auto-induction and significant ethnic variability in its pharmacokinetics (PK). These complexities are further exacerbated in HIV-TB co-infected patients, where nevirapine is often co-administered with rifampicin/isoniazid-based anti-tuberculosis (TB) therapies. Rifampicin, a strong CYP3A4 inducer and moderate CYP2B6 inducer, and isoniazid, a moderate CYP3A4 inhibitor, create intricate drug interactions that challenge optimal nevirapine dosing strategies, leading to clinical uncertainty and debate. We developed a physiologically based pharmacokinetic (PBPK) model for nevirapine that integrates auto-induction, drug interactions, and ethnic variability. The model successfully captured the time-dependent PK of nevirapine across Caucasian, African, and Asian populations, with and without rifampicin/isoniazid co-administration. Simulations revealed that the standard nevirapine regimen (200 mg QD lead-in, 200 mg BID maintenance) was appropriate for Caucasian and African HIV patients but required adjustment to 150 mg QD lead-in and 150 mg BID maintenance for Asians to minimize toxicity. In HIV-TB co-infected patients, nevirapine co-administration with rifampicin/isoniazid was unsuitable for Caucasians due to sub-therapeutic levels. For Africans, an increased regimen (200 mg QD lead-in, 300 mg BID maintenance) was recommended, while drug interactions did not alter the reduced dosing recommendation of nevirapine for Asians. Our findings underscore the necessity of incorporating ethnic variability and drug interaction profiles into nevirapine dosing strategies to optimize therapeutic efficacy and safety in HIV and HIV-TB co-infected patients. Graphical Abstract
  PubDate: 2025-03-12
Uniform Spray Dried Loxapine Microparticles Potentially for Nasal
Delivery: Exploring Discriminatory In Vitro Release Evaluation Methods
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  Abstract: This study aimed to develop suitable in vitro evaluation methods for the release behavior of nasal powders (NPs). We synthesized a range of standardized microparticles with adjustable size and morphology by co-spray-drying loxapine succinate (LOX) and gelatin (GEL) using an ethanol/water solvent mixture in a self-designed micro-fluidic jet spray dryer (MFJSD). The influence of the LOX/GEL mass ratio and solvent composition on particle characteristics, including size, morphology, and crystalline properties, was systematically investigated. In vitro release profiles of NPs were thoroughly assessed across different release medium, apparatus, and membranes. The modified Transwell® system, utilizing simulated nasal electrolyte solution (SNES) as the release medium, was identified as the most effective in distinguishing the performance of microparticles with diverse attributes. Furthermore, the impact of particle size, morphology, and crystalline properties on in vitro release profiles was discussed. This research presents a robust methodology for the in vitro evaluation of NPs release profiles and provides a practical approach for the rational fabrication of high-quality NPs products. Graphical Abstract
  PubDate: 2025-03-12

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