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Characterization of the pharmacokinetics and biodistribution of therapeutic proteins (TPs) is a hot topic within the pharmaceutical industry, particularly with an ever-increasing catalog of novel modality TPs. Here, we review the current practices, and provide a summary of extensive cross-company discussions as well as a survey completed by International Consortium for Innovation and Quality members on this theme. A wide variety of in vitro, in vivo and in silico techniques are currently used to assess pharmacokinetics and biodistribution of TPs, and we discuss the relevance of these from an industry perspective, focusing on pharmacokinetic/pharmacodynamic understanding at the preclinical stage of development, and translation to human. We consider that the 'traditional in vivo biodistribution study' is becoming insufficient as a standalone tool, and thorough characterization of the interaction of the TP with its target(s), target biology, and off-target interactions at a microscopic scale are key to understand the overall biodistribution on a full-body scale. Our summary of the current challenges and our recommendations to address these issues could provide insight into the implementation of best practices in this area of drug development, and continued cross-company collaboration will be of tremendous value. SIGNIFICANCE STATEMENT: The Innovation and Quality Consortium Translational and ADME Sciences Leadership Group working group for the absorption, distribution, metabolism, and excretion of therapeutic proteins evaluates the current practices and challenges in characterizing the pharmacokinetics and biodistribution of therapeutic proteins during drug development, and proposes recommendations to address these issues. Incorporating the in vitro, in vivo and in silico approaches discussed herein may provide a pragmatic framework to increase early understanding of pharmacokinetic/pharmacodynamic relationships, and aid translational modeling for first-in-human dose predictions., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

A review of the use of microdoses and isotopic microtracers for clinical intravenous pharmacokinetic (i.v. PK) data provision is presented. The extent of application of the varied approaches available and the relative merits of each are highlighted with the aim of assisting practitioners in making informed decisions on the most scientifically appropriate design to adopt for any given new drug in development. It is envisaged that significant efficiencies will be realized as i.v. PK data in humans becomes more routinely available for suitable assets in early development, than has been the case prior to the last decade., (© 2023 GSK Research and Development Ltd. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Objective: Drug dosing should ideally be based on the drug concentrations at the target site, which, for most drugs, corresponds to the tissue. The exact influence of growth and development on drug tissue distribution is unclear. This systematic review compiles the current knowledge on the tissue distribution of systemically applied drugs in children, with the aim to identify priorities in tissue pharmacokinetic (PK) research in this population., Methods: A systematic literature search was performed in the MEDLINE and Embase databases., Results: Forty-two relevant articles were identified, of which 71% investigated antibiotics, while drug classes from the other studies were anticancer drugs, antifungals, anthelmintics, sedatives, thyreostatics, immunomodulators, antiarrhythmics, and exon skipping therapy. The majority of studies (83%) applied tissue biopsy as the sampling technique. Tonsil and/or adenoid tissue was most frequently examined (70% of all included patients). The majority of studies had a small sample size (median 9, range 1-93), did not include the youngest age categories (neonates and infants), and were of low reporting quality. Due to the heterogeneous data from different study compounds, dosing schedules, populations, and target tissues, the possibility for comparison of PK data between studies was limited., Conclusion: The influence of growth and development on drug tissue distribution continues to be a knowledge gap, due to the paucity of tissue PK data in children, especially in the younger age categories. Future research in this field should be encouraged as techniques to safely investigate drug tissue disposition in children are available., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The objective of the present work is to evaluate the ability of the radiolabeled PAMAM dendrimers (polyamidoamine) towards facilitating the delivery of an in‐house synthesized porphyrin derivative in the tumorous lesions to evaluate their candidature for possible application in endo‐radionuclide therapy. For this, PAMAM particles were conjugated with a porphyrin derivative namely, 5,10,15,20‐tetrakis‐(4‐carboxymethyleneoxyphenyl)porphyrin (STAP), synthesized in‐house following a two‐step reaction. The average number of porphyrin molecules loaded per PAMAM particle was evaluated using ultraviolet‐visible spectrophotometry and was found to be approximately 2. STAP conjugated PAMAM particles were further conjugated with p‐NCS‐benzyl‐DOTA (subsequently referred as DOTA) to facilitate radiolabeling with 177Lu. On an average, two p‐NCS‐benzyl‐DOTA molecules were observed to be attached per PAMAM‐STAP particle. DOTA‐PAMAM‐STAP conjugate was radiolabeled with 177Lu with a final radiochemical purity of >95%, which was determined by paper chromatography using two different mobile phases viz. 0.1 M sodium citrate buffer (pH 5.0) and 10 mM DTPA. Biological behavior of [177Lu]Lu‐DOTA‐PAMAM‐STAP conjugate was investigated in fibrosarcoma bearing Swiss mice model wherein accumulation of radiolabeled particles was observed in liver, GIT, spleen, and kidneys at 3 h post‐administration. However, accumulated activity exhibited rapid clearance from majority of the organs at 24 h post‐administration. [177Lu]Lu‐DOTA‐PAMAM‐STAP conjugate exhibited an appreciable uptake in tumor mass [6.09 ± 1.22 percentage injected activity/organ (% IA/organ)] at 3 h post‐administration (p.i.) which was found to reduce to 1.05 ± 0.13 % IA/organ at 24 h post‐administration. The results obtained in biodistribution studies were further corroborated through scintigraphic imaging performed in the same animal model. Despite of an appreciable accumulation in tumor mass, the lower retention of the [177Lu]Lu‐DOTA‐PAMAM‐STAP conjugate therein, at longer time point (24 h p.i.) may limit its possible potential as a radio‐therapeutic agent and indicates towards need for further structural manoeuvring to attain favorable in vivo performance. [ABSTRACT FROM AUTHOR]

The current approach to selection of a population PK/PD model is inherently flawed as it fails to account for interactions between structural, covariate, and statistical parameters. Further, the current approach requires significant manual and redundant model modifications that heavily lend themselves to automation. Within the discipline of numerical optimization it falls into the "local search" category. Genetic algorithms are a class of algorithms inspired by the mathematics of evolution. GAs are general, powerful, robust algorithms and can be used to find global optimal solutions for difficult problems even in the presence of non-differentiable functions, as is the case in the discrete nature of including/excluding model components in search of the best performing mixed-effects PK/PD model. A genetic algorithm implemented in an R-based NONMEM workbench for identification of near optimal models is presented. In addition to the GA capabilities, the workbench supports modeling efforts by: (1) Organizing and displaying models in tabular format, allowing the user to sort, filter, edit, create, and delete models seamlessly, (2) displaying run results, parameter estimates and precisions, (3) integrating xpose4 and PsN to facilitate generation of model diagnostic plots and run PsN scripts, (4) running regression models between post-hoc parameter estimates and covariates. This approach will further facilitate the scientist to shift efforts to focus on model evaluation, hypotheses generation, and interpretation and applications of resulting models., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Per the well‐known resistance of hepatitis B virus to nucleoside/nucleotide analogs, alternative treatment options with higher resistance barriers have been approved for use in both treatment‐naïve and lamivudine‐resistant hepatitis B virus infections. This phase I study was conducted in adults with normal and impaired renal function to evaluate the effect of renal impairment on the pharmacokinetics of besifovir, a prodrug of an acyclic nucleotide phosphonate, that is mainly cleared via renal excretion. An open‐label, single‐dose parallel‐group clinical study was conducted in subjects with normal renal function and mild, moderate, and severe renal impairment. Subjects received a single oral dose of besifovir dipivoxil 150 mg, and serial blood and urine samples were collected for up to 72 hours after dosing to assess the pharmacokinetic characteristics of besifovir. The extent of plasma exposure of besifovir, detected as its major and active metabolites, LB80331 and LB80317, respectively, increased with worsening renal function. Compared to the subjects with normal renal function, the mean areas under the concentration‐time curves of LB80331 increased by 1.5‐, 2.5‐, and 4.5‐fold in subjects with mild, moderate, and severe impairment, respectively. LB80317 showed a 1.8‐, 3.2‐, and 6.2‐fold increase in subjects with mild, moderate, and severe renal impairment compared to those with normal function. The ratios of LB80331 renal clearance and the average estimated glomerular filtration rate of each renal impairment group with respect to the normal group were similar. The increase in plasma exposure and decrease in renal clearance suggest the need to adjust dosage regimens in patients with moderate to severe renal impairment. [ABSTRACT FROM AUTHOR]

Introduction and aim. Lung cancer is a major public health concern around the world and is responsible for a significant number of deaths. Most lung cancers are detected in advanced stages due to a lack of early-stage diagnosis, limiting the available therapeutic options. Unfortunately, conventional lung cancer treatments are frequently linked with side effects because they are not target-specific and can also harm neighboring healthy body cells. Nanotechnology has the potential to significantly add to the development of differentiated products and the improvement of patient outcomes. Clinical research has shown that nanomedicines enhance the pharmacokinetics and biodistribution of therapeutic agents while lowering their systemic toxicity. The objective of this review was to provide a summary of the current research on nanomedicines that have been clinically approved for the treatment of lung cancer. Material and methods. In February 2023, a PubMed literature search was conducted. The phrase "nanomedicines in lung cancer" was entered into the PubMed search engine. Articles published within the last five years were taken into account. To determine eligibility, the abstract of each study was reviewed. Finally, the full texts of selected articles were obtained and reviewed. Analysis of literature. The analysis of the literature revealed that nanomedicines offer significant advantages in lung cancer treatment, including improved pharmacokinetics, enhanced drug targeting to tumor tissues, and reduced systemic toxicity. However, further research is warranted to fully realize the potential of nanomedicines and optimize their clinical application. This analysis provides valuable insights into the current state of knowledge and highlights the need for continued exploration in this promising field of research. Conclusion. In summary, nanomedicine precisely targets tumor tissue and delivers drugs in a controlled and efficient manner. This is a novel strategy to overcome the existing limitations in the treatment of lung cancer. Further research is needed in this field as it is a promising area of lung cancer treatment. [ABSTRACT FROM AUTHOR]

Oritavancin (ORI) is a semisynthetic lipoglycopeptide approved as a single 1200 mg dose intravenous infusion for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by Gram-positive organisms in adults. The pharmacokinetic/pharmacodynamic (PK/PD) linear kinetic profile and long terminal half-life (~393 h) of ORI make it therapeutically attractive for the treatment of other Gram-positive infections for which prolonged therapy is needed. Multidose regimens are adopted in real-world clinical practice with promising results, but aggregated efficacy data are still lacking. A comprehensive search on PubMed/Medline, Scopus, Cochrane and Google Scholar databases was performed to include papers published up to the end of January 2023. All articles on ORI multiple doses usage, including case reports, with quantitative data and relevant clinical information were included. Two reviewers independently assessed papers against the inclusion/exclusion criteria and for methodological quality. Differences in opinion were adjudicated by a third party. From 1751 potentially relevant papers identified by this search, a total of 16 studies met the inclusion criteria and were processed further in the final data analysis. We extracted data concerning clinical response, bacteriologic response, mortality and adverse events (AEs). From the 16 included papers, 301 cases of treatment with multidose ORIs were identified. Multidose regimens comprised an initial ORI dose of 1200 mg followed by 1200 mg or 800 mg subsequent doses with a varying total number and frequency of reinfusions. The most often treated infections and isolates were osteomyelitis (148; 54.4%), ABSSSI (35; 12.9%) and cellulitis (14; 5.1%); and MRSA (121), MSSA (66), CoNS (17), E. faecalis (13) and E. faecium (12), respectively. Clinical cure and improvement by multidose ORI regimens were observed in 85% (231/272) and 8% (22/272) patients, respectively. Multidose ORI was safe and well tolerated; the most frequent AEs were infusion-related reactions and hypoglycemia. A multidose ORI regimen may be beneficial in treating other Gram-positive infections besides ABSSSIs, with a good safety profile. Further studies are warranted to ascertain the superiority of one multidose ORI scheme or posology over the other. [ABSTRACT FROM AUTHOR]

Introduction: Traditionally, health ministries implement mass drug administration programmes for each neglected tropical disease (NTD) as separate and distinct campaigns. Many NTDs have overlapping endemicity suggesting co-administration might improve programme reach and efficiency, helping accelerate progress towards 2030 targets. Safety data are required to support a recommendation to undertake co-administration. Methodology: We aimed to compile and summarize existing data on co-administration of ivermectin, albendazole and azithromycin, including both data on pharmacokinetic interactions and data from previous experimental and observational studies conducted in NTD-endemic populations. We searched PubMed, Google Scholar, research and conference abstracts, gray literature, and national policy documents. We limited the publication language to English and used a search period from January 1st, 1995 through October 1st, 2022. Search terms were: azithromycin and ivermectin and albendazole, mass drug administration co-administration trials, integrated mass drug administration, mass drug administration safety, pharmacokinetic dynamics, and azithromycin and ivermectin and albendazole. We excluded papers if they did not include data on co-administration of azithromycin and both albendazole and ivermectin, or azithromycin with either albendazole or ivermectin alone. Results: We identified a total of 58 potentially relevant studies. Of these we identified 7 studies relevant to the research question and which met our inclusion criteria. Three papers analyzed pharmacokinetic and pharmacodynamic interactions. No study found evidence of clinically significant drug-drug interactions likely to impact safety or efficacy. Two papers and a conference presentation reported data on the safety of combinations of at least two of the drugs. A field study in Mali suggested the rates of adverse events were similar with combined or separate administration, but was underpowered. A further field study in Papua New Guinea used all three drugs as part of a four-drug regimen also including diethylcarbamazine; in this setting, co-administration appeared safe but there were issues with the consistency in how adverse events were recorded. Conclusion: There are relatively limited data on the safety profile of co-administering ivermectin, albendazole and azithromycin as an integrated regimen for NTDs. Despite the limited amount of data, available evidence suggests that such a strategy is safe with an absence of clinically important drug-drug interactions, no serious adverse events reported and little evidence for an increase in mild adverse events. Integrated MDA may be a viable strategy for national NTD programmes. Author summary: Treatment of the whole community (mass drug administration, MDA) has been a major intervention strategy against many neglected tropical diseases (NTDs) over the last decade. Normally health ministries deliver individual MDA rounds targeting specific NTDs. This multiplies the training, transport and time burden for local health service personnel in districts in which several NTDs are present, imposing considerable financial and human resource costs to health ministries and their partners, and causing requiring repeated disruption to the daily life of communities receiving MDA. Delivering MDA for several NTDs at one time could improve the efficiency of NTD programmes. We reviewed existing data on the safety and feasibility of combining MDA of albendazole, ivermectin and azithromycin into a single co-delivered MDA. Several studies had evaluated if taking these drugs at the same time changed drug levels in recipients' blood; these studies concluded that there was not an important difference in blood drug levels comparing instances when the medicines were taken separately to instances when they were taken at the same time. Two non-randomised studies assessed side effects experienced by people taking combinations of the three drugs and suggested doing so was safe. One small study in Mali had assessed combining all three drugs and also suggested this was safe but was too small to give a definitive answer. Two studies in Papua New Guinea assessed all three drugs being taken together in combination with a fourth drug, diethylcarbamazine. These studies also suggest co-administration was safe overall. Most of the identified studies had some methodological shortcomings, such as small sample sizes or issues with the way adverse events were recorded. Overall, the data suggest co-administration of azithromycin, ivermectin and albendazole is viable, but larger safety studies are needed. [ABSTRACT FROM AUTHOR]

Recently, we have proposed simple methodology to derive clearance and rate constant equations, independent of differential equations, based on Kirchhoff's Laws, a common methodology from physics used to describe rate-defining processes either in series or parallel. Our approach has been challenged in three recent publications, two published in this journal, but notably what is lacking is that none evaluate experimental pharmacokinetic data. As reviewed here, manuscripts from our laboratory have evaluated published experimental data, demonstrating that the Kirchhoff's Laws approach explains (1) why all of the experimental perfused liver clearance data appear to fit the equation that was previously believed to be the well-stirred model, (2) why linear pharmacokinetic systemic bioavailability determinations can be greater than 1, (3) why renal clearance can be a function of drug input processes, and (4) why statistically different bioavailability measures may be found for urinary excretion versus systemic concentration measurements. Our most recent paper demonstrates (5) how the universally accepted steady-state clearance approach used by the field for the past 50 years leads to unrealistic outcomes concerning the relationship between liver-to-blood Kp uu and hepatic availability F H , highlighting the potential for errors in pharmacokinetic evaluations based on differential equations. The Kirchhoff's Laws approach is applicable to all pharmacokinetic analyses of quality experimental data, those that were previously adequately explained with present pharmacokinetic theory, and those that were not . The publications that have attempted to rebut our position do not address unexplained experimental data, and we show here why their analyses are not valid. SIGNIFICANCE STATEMENT: The Kirchhoff's Laws approach to deriving clearance equations for linear systems in parallel or in series, independent of differential equations, successfully describes published pharmacokinetic data that has previously been unexplained. Three recent publications claim to refute our proposed methodology; these publications only make theoretical arguments, do not evaluate experimental data, and never demonstrate that the Kirchhoff methodology provides incorrect interpretations of experimental pharmacokinetic data, including statistically significant data not explained by present pharmacokinetic theory. We demonstrate why these analyses are invalid., (Copyright © 2024 by The Author(s).)

First-order compartment models are common tools for modelling many biological processes, including pharmacokinetics. Given the compartments and the transfer rates, solutions for the time-dependent quantity (or concentration) curves can normally be described by a sum of exponentials. This paper investigates cases that go beyond simple sums of exponentials. With specific relations between the transfer rate constants, two exponential rate constants can be equal, in which case the normal solution cannot be used. The conditions for this to occur are discussed, and advice is provided on how to circumvent these cases. An example of an analytic solution is given for the rare case where an exact equality is the expected result. Furthermore, for models with at least three compartments, cases exist where the solution to a real-valued model involves complex-valued exponential rate constants. This leads to solutions with an oscillatory element in the solution for the tracer concentration, i.e., there are cases where the solution is not a simple sum of (real-valued) exponentials but also includes sine and cosine functions. Detailed solutions for three-compartment cases are given. As a tentative conclusion of the analysis, oscillatory solutions appear to be tied to cases with a cyclic element in the model itself., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In the realm of pharmaceutical advancement, the transformative prowess of nanotechnology shines through its precision-targeted drug delivery and amplified therapeutic effects. This paper ventures into the realm of radiolabeling techniques for unraveling the intricate choreography of drug kinetics within the bloodstream which encompass the delicate stages of absorption, distribution, metabolism, and excretion. Through the magical lens of the radiolabel, a real-time spectacle unfolds, providing invaluable insights into the safety and efficacy of nanomedicine interventions. Amid the labyrinthine complexities of drug-organism interactions and the lack of universal protocols for nanomedicine preparation, radiolabeling technology has emerged as a guiding constellation. The paper systematically assesses the methods commonly employed for pharmacokinetic studies, delves into the manifold advantages and techniques of radiolabel methods within the nanomedicine landscape, closely examines their application across a spectrum of pharmacokinetic studies and thoughtfully addresses the challenges they may pose. Embark on this illuminating odyssey--a journey that peers into the microcosm of nanomedicine, deciphering its dynamic interplay within the bloodstream through the luminary insights of radiolabeled tracing techniques. [ABSTRACT FROM AUTHOR]

This commentary further reflects on the paper of De Sutter et al. on predicting volume of distribution in neonates, and the performance of physiologically based pharmacokinetic models We hereby stressed the add on value to collaborate on real world data to further close this knowledge gap. We illustrated this by weight distribution characteristics in breastfed (physiology) and in asphyxiated (pathophysiology), with additional reflection on their kidney and liver function. [ABSTRACT FROM AUTHOR]

Taxus, a rare and protected genus predominantly distributed across the Northern Hemisphere’s temperate regions, has garnered global attention due to its significant potential in medical research and pharmaceutical development, bolstered by advancements in cultivation techniques and medical technology. This review primarily focuses on the chemical constituents and pharmacological activities of Taxus, underscoring the progress and potential of these components in clinical applications. Recent studies have revealed that Taxus contains not only taxane active components but also flavonoids and polysaccharides with distinct activities. These compounds from Taxus exhibit potent antitumor, anti-inflammatory, immunomodulatory, antibacterial, and antidiabetic properties with evident mechanisms of action. Notably, the representative compound, paclitaxel, has demonstrated significant efficacy in treating various cancers, such as ovarian, breast, and lung cancer. This paper also reviews the basic situation of Taxus drug formulations, with extracts primarily administered orally and monomeric taxanes typically via injection, reflecting a mature development stage with ongoing research into oral formulations. Finally, this review summarizes the pharmacokinetic characteristics of crucial compounds in Taxus, including their absorption, distribution, metabolism, and excretion patterns in the human body. These pharmacokinetic profiles provide crucial guidance for evaluating the overall dosing regimen of Taxus and its components. The paper concludes with a forward-looking analysis of the potential applications of these compounds in disease treatment, envisioning their role in the future of medical and pharmaceutical advancements. [ABSTRACT FROM AUTHOR]

Leonurine is an alkaloid unique to the Leonurus genus, which has many biological activities, such as uterine contraction, anti-inflammation, anti-oxidation, regulation of cell apoptosis, anti-tumor, angiogenesis, anti-platelet aggregation, and inhibition of vasoconstriction. This paper summarizes the extraction methods, synthetic pathways, biosynthetic mechanisms, pharmacokinetic properties, pharmacological effects in various diseases, toxicology, and clinical trials of leonurine. To facilitate a successful transition into clinical application, intensified efforts are required in several key areas: structural modifications of leonurine to optimize its properties, comprehensive pharmacokinetic assessments to understand its behavior within the body, thorough mechanistic studies to elucidate how it works at the molecular level, rigorous safety evaluations and toxicological investigations to ensure patient wellbeing, and meticulously conducted clinical trials to validate its efficacy and safety profile. [ABSTRACT FROM AUTHOR]

This paper presents a thorough examination for drug release from a polymeric matrix to improve understanding of drug release behavior for tissue regeneration. A comprehensive model was developed utilizing mass transfer and machine learning (ML). In the machine learning section, three distinct regression models, namely, Decision Tree Regression (DTR), Passive Aggressive Regression (PAR), and Quadratic Polynomial Regression (QPR) applied to a comprehensive dataset of drug release. The dataset includes r(m) and z(m) inputs, with corresponding concentration of solute in the matrix (C) as response. The primary objective is to assess and compare the predictive performance of these models in finding the correlation between input parameters and chemical concentrations. The hyperparameter optimization process is executed using Sequential Model-Based Optimization (SMBO), ensuring the robustness of the models in handling the complexity of the controlled drug release. The Decision Tree Regression model exhibits outstanding predictive accuracy, with an R2 score of 0.99887, RMSE of 9.0092E-06, MAE of 3.51486E-06, and a Max Error of 6.87000E-05. This exceptional performance underscores the model's capability to discern intricate patterns within the drug release dataset. The Passive Aggressive Regression model, while displaying a slightly lower R2 score of 0.94652, demonstrates commendable predictive capabilities with an RMSE of 6.0438E05, MAE of 4.82782E-05, and a Max Error of 2.36600E-04. The model's effectiveness in capturing non-linear relationships within the dataset is evident. The Quadratic Polynomial Regression model, designed to accommodate quadratic relationships, yields a noteworthy R2 score of 0.95382, along with an RMSE of 5.6655E-05, MAE of 4.49198E-05, and a Max Error of 1.86375E-04. These results affirm the model's proficiency in capturing the inherent complexities of the drug release system. [ABSTRACT FROM AUTHOR]

A novel cholic acid-conjugated carboplatin (CP-CA) is developed as a liver-targeting prodrug of carboplatin (CP) for liver cancer. Instead of using CP as a raw material, CP-CA was synthesized simultaneously. This paper is focused on the comparison of CP-CA and CP with respect to their pharmacokinetic (PK) and tissue distribution profiles in rats after their intravenous administration. Additionally, their uptake by human liver tumor cell Huh7 and normal human liver cell HL7702 are investigated. The inductively coupled plasma mass spectrometry (ICP-MS) method is applied for the determination of platinum in plasma, tissues, and cells. The PK results show that both the AUC0–t and AUC0–∞ data on Pt for CP-CA are significantly higher than those for CP (p < 0.01), indicating that the plasma exposure of CP-CA is significantly higher than that of CP. The CL1, Vd1, and Vd2 data on Pt for CP-CA are significantly lower than those for CP (p < 0.01), while the MRT0–t is significantly higher (p < 0.01), which is possibly related to a higher PPBR, and can strongly support the higher AUC0–t and AUC0–∞ of Pt for CP-CA compared to for CP. The tissue distribution results show that CP-CA is mainly distributed and accumulated in the liver after its intravenous administration to rats, revealing its liver-targeting profile. Compared to CP, CP-CA is more easily taken up by human liver cancer cells and normal human liver cells. The results suggest that CP-CA has a potential for further development as a new prodrug specific to liver cancer. [ABSTRACT FROM AUTHOR]

In the past decade, only a small number of papers have elaborated on the application of physiologically based pharmacokinetic (PBPK) modeling across different areas. In this review, an in-depth analysis of the distribution of PBPK modeling in relation to its application in various research topics and model validation was conducted by text mining tools. Orange 3.32.0, an open-source data mining program was used for text mining. PubMed was used for data retrieval, and the collected articles were analyzed by several widgets. A total of 2699 articles related to PBPK modeling met the predefined criteria. The number of publications per year has been rising steadily. Regarding the application areas, the results revealed that 26% of the publications described the use of PBPK modeling in early drug development, risk assessment and toxicity assessment, followed by absorption/formulation modeling (25%), prediction of drug-disease interactions (20%), drug-drug interactions (DDIs) (17%) and pediatric drug development (12%). Furthermore, the analysis showed that only 12% of the publications mentioned model validation, of which 51% referred to literature-based validation and 26% to experimentally validated models. The obtained results present a valuable review of the state-of-the-art regarding PBPK modeling applications in drug discovery and development and related fields. [ABSTRACT FROM AUTHOR]

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature. [ABSTRACT FROM AUTHOR]

Measurement of pre‐dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration—time curve (AUC).However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long‐term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed.In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients. [ABSTRACT FROM AUTHOR]

The purpose of this paper was to investigate the anti-inflammatory and anti-angiogenic activities of sulfated polysaccharide from C. tomentosum (PCT) using carrageenan (CARR)-induced paw edema in a rat model and anti-vasculogenic activity on a chorioallantoic membrane assay (CAM) model. Based on in vitro tests of anti-radical, total antioxidant, and reducing power activities, PCT presents a real interest via its antioxidant activity and ability to scavenge radical species. The in vivo pharmacological tests suggest that PCT possesses anti-inflammatory action by reducing paw edema and leukocyte migration, maintaining the redox equilibrium, and stabilizing the cellular level of several pro-/antioxidant system markers. It could significantly decrease the malondialdehyde levels and increase superoxide dismutase, glutathione peroxidase, and glutathione activities in local paw edema and erythrocytes during the acute inflammatory reaction of CARR. PCT pretreatment was effective against DNA alterations in the blood lymphocytes of inflamed rats and reduced the hematological alteration by restoring blood parameters to normal levels. The anti-angiogenic activity results revealed that CAM neovascularization, defined as the formation of new vessel numbers and branching patterns, was decreased by PCT in a dose-dependent manner, which supported the in silico bioavailability and pharmacokinetic findings. These results indicated the therapeutic effects of polysaccharides from C. tomentosum and their possible use as anti-proliferative molecules based on their antioxidant, anti-inflammatory, and anti-angiogenic activities. [ABSTRACT FROM AUTHOR]

Pharmacometric modelling plays a key role in both the design and analysis of regulatory trials in paediatric drug development. Studies in adults provide a rich source of data to inform the paediatric investigation plans, including knowledge on drug pharmacokinetics (PK), safety and efficacy. In children, drug disposition differs widely from birth to adolescence but extrapolating adult to paediatric PK, safety and efficacy either with pharmacometric or physiologically based approaches can help design or in some cases reduce the need for clinical studies. Aspects to consider when extrapolating PK include the maturation of drug metabolizing enzyme expression, glomerular filtration, drug excretory systems, and the expression and activity of specific transporters in conjunction with other drug properties such as fraction unbound. Knowledge of these can be used to develop extrapolation tools such as allometric scaling plus maturation functions or physiologically based PK. PK/pharmacodynamic approaches and well‐designed clinical trials in children are of key importance in paediatric drug development. In this white paper, state‐of‐the‐art of current methods used for paediatric extrapolation will be discussed. This paper is part of a conect4children implementation of innovative methodologies including pharmacometric and physiologically based PK modelling in clinical trial design/paediatric drug development through dissemination of expertise and expert advice. The suggestions arising from this white paper should define a minimum set of standards in paediatric modelling and contribute to the regulatory science. [ABSTRACT FROM AUTHOR]

Public policies and regulations strongly influence research and manufacturing in pharmaceutical sector. Therefore, it is of critical importance that these policies and regulations are of high quality as well as appropriately balanced between general rules and detailed solutions. The process of public consultations prolongs adoption of novel documents. On the other hand, comments from different stakeholders like academia, industry, public administration and patients allow 360-degree critical evaluation of the document and a better understanding of the topic. This mini-review summarizes the contributions of numerous members of ORBIS project team in open consultations of draft regulatory documents published by European Medicines Agency (EMA) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ORBIS project feedback on the Pharmaceutical Strategy for Europe is also presented. ORBIS project members contributed to open consultations of two ICH draft guidelines, and three EMA draft documents. ORBIS project was also active during the European Commission's efforts to develop Pharmaceutical Strategy for Europe. The interaction between representatives of academic and industrial sectors allowed to form balanced comments. We hope that this paper will inspire more researchers to participate in future open consultations on public policies. [ABSTRACT FROM AUTHOR]

We present a novel Pharmacokinetic/Pharmacodynamic (PK/PD) model for the induction phase of anesthesia, incorporating the ψ-Caputo fractional derivative. By employing the Picard iterative process, we derive a solution for a nonhomogeneous ψ-Caputo fractional system to characterize the dynamical behavior of the drugs distribution within a patient's body during the anesthesia process. To explore the dynamics of the fractional anesthesia model, we perform numerical analysis on solutions involving various functions of ψ and fractional orders. All numerical simulations are conducted using the MATLAB computing environment. Our results suggest that the ψ functions and the fractional order of differentiation have an important role in the modeling of individual-specific characteristics, taking into account the complex interplay between drug concentration and its effect on the human body. This innovative model serves to advance the understanding of personalized drug responses during anesthesia, paving the way for more precise and tailored approaches to anesthetic drug administration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Inappropriate expression of histone deacetylase (HDAC-6) and deregulation of the phosphatidylinositol 3-kinase (PI3K) signalling pathway are common aberrations observed in cancers. LASSBio-2208, has been previously described as a dual inhibitor in the nanomolar range of HDAC-6 and PI3Kα and is three times more potent in inhibiting HDAC-6. In this paper we described the cytotoxic and antiproliferative potency of LASSBio-2208 on different tumour cell lines, its possible synergism effect in association with PI3K and HDAC-6 inhibitors, and its drug metabolism and pharmacokinetics (DMPK) in vitro profile. Our studies have demonstrated that LASSBio-2208 has moderate cytotoxic potency on breast cancer cell line MCF-7 (IC50 = 23 µM), human leukaemia cell line CCRF-CEM (IC50 = 8.54 µM) and T lymphoblast cell line MOLT-4 (IC50 = 7.15 µM), with no cytotoxic effect on human peripheral blood mononuclear cells (hPBMC). In addition, it has a good antiproliferative effect on MCF-7 cells (IC50 = 5.44 µM), low absorption by parallel artificial membrane permeability—gastrointestinal tract (PAMPA—GIT) and low permeation by parallel artificial membrane permeability—blood–brain barrier (BBB) (PAMPA—BBB), exhibiting high metabolic stability in rat plasma. Moreover, LASSBio-2208 exhibited synergism when combined with getadolisib and tubastatin A, using the concentrations corresponding to their CC50 values on MOLT-4 and CCRF-CEM cells. [ABSTRACT FROM AUTHOR]

We have developed a method to determine the limit of detection (LoD) for quantitative measurement of exogenous analytes in the outer layer of the human skin by in vivo confocal Raman spectroscopy. The method is in accordance with the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use that have been adopted by regulatory authorities such as the American Food and Drug Administration and the European Medicines Agency. The method can be applied in silico so that the limit of detection can be assessed before starting a skin penetration study, for example, in areas of pharmaceutical formulation, pharmacokinetics, or toxicokinetics. This can significantly reduce the need for expensive and time-consuming feasibility studies. This paper describes the method to calculate this LoD as well as the experimental and methodological factors that can influence the calculation of the LoD. [ABSTRACT FROM AUTHOR]

Thermal deformation of the rotor is a critical factor leading to radial air leakage in rotary air preheaters. However, previous studies have not comprehensively established the correlation between rotor thermal deformation during thermal operation and radial air leakage. This study addresses this gap by introducing a novel model for calculating radial air leakage, incorporating the thermal deformation of the rotor. To achieve this, we selected a three-section rotary air preheater from a 330 MW coal-fired unit boiler for investigation. This research begins by constructing a heat transfer–structure coupled numerical simulation model using Fluent and ANSYS Workbench. This model is employed to analyze the thermal deformation of the rotor under varying unit power generation loads. This paper meticulously examines the thermal deformation patterns of the rotor in diverse circumstances, explores their impact on air leakages, and provides a comprehensive analysis of air leakage fluctuations in different ducts. The influence of rotor thermal deformation on the local radial leak characteristics is ultimately established. The results indicate that incorporating the impact of preheater thermal deformation into the examination of preheater air leakage enhances the model's capacity to accurately simulate values of leakage distribution at various cell clearances. This research concludes by offering recommendations for effectively managing hot end radial air leakage in preheater systems, providing valuable insights for the design and adjustment of sealing systems. [ABSTRACT FROM AUTHOR]

Broad-spectrum histone deacetylase inhibitors (HDACi) have excellent anti-tumor effects, such as abexinostat, which was a novel oral HDACi that was widely used in clinical treatment. The purpose of this study was to establish a rapid and reliable method for the detection of abexinostat concentrations in rat plasma using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The mobile phase we used was acetonitrile and 0.1% formic acid, and the internal standard (IS) was givinostat. Selective reaction monitoring (SRM) was used for detection with ion transitions at m/z 397.93 → 200.19 for abexinostat and m/z 422.01 → 186.11 for givinostat, respectively. The intra-day and inter-day precision of abexinostat were less than 11.5% and the intra-day and inter-day accuracy ranged from − 10.7% to 9.7% using this method. During the analysis process, the stability of the test sample was reliable. In addition, the recovery and matrix effects of this method were within acceptable limits. Finally, the method presented in this paper enabled accurate and quick determination of abexinostat levels in rat plasma from the pharmacokinetic study following gavage at a dose of 8.0 mg/kg abexinostat. [ABSTRACT FROM AUTHOR]

Introduction: The cytochrome P450 enzyme subfamilies, including CYP3A4 and CYP1A2, have a major role in metabolism of a range of drugs including several anti-cancer treatments. Many factors including environmental exposures, diet, diseaserelated systemic inflammation and certain genetic polymorphisms can impact the activity level of these enzymes. As a result, the net activity of each enzyme subfamily can vary widely between individuals and in the same individual over time. This variability has potential major implications for treatment efficacy and risk of drug toxicity, but currently no assays are available for routine use to guide clinical decision-making. Methods: To address this, a mass spectrometry-based method to measure activities of CYP3A4, CYP1A2 was adapted and tested in free-living participants. The assay results were compared with the predicted activity of each enzyme, based on a self-report tool capturing diet, medication, chronic disease state, and tobacco usage. In addition, a feasibility test was performed using a low-volume dried blood spots (DBS) on two different filter-paper supports, to determine if the same assay could be deployed without the need for repeated standard blood tests. Results: The results confirmed the methodology is safe and feasible to perform in free-living participants using midazolam and caffeine as test substrates for CYP3A4 and CYP1A2 respectively. Furthermore, though similar methods were previously shown to be compatible with the DBS format, the assay can also be performed successfully while incorporating glucuronidase treatment into the DBS approach. The measured CYP3A4 activity score varied 2.6-fold across participants and correlated with predicted activity score obtained with the self-report tool. The measured CYP1A2 activity varied 3.5-fold between participants but no correlation with predicted activity from the self-report tool was found. Discussion: The results confirm the wide variation in CYP activity between individuals and the important role of diet and other exposures in determining CYP3A4 activity. This methodology shows great potential and future crosssectional and longitudinal studies using DBS are warranted to determine how best to use the assay results to guide drug treatments. [ABSTRACT FROM AUTHOR]

Unesbulin is being investigated in combination with dacarbazine (DTIC) as a potential therapeutic agent in patients with advanced leiomyosarcoma (LMS). This paper reports the pharmacokinetics (PK) of unesbulin, DTIC, and its unreactive surrogate metabolite 5‐aminoimidazole‐4‐carboxamide (AIC) in 29 patients with advanced LMS. Drug interactions between DTIC (and AIC) and unesbulin were evaluated. DTIC (1000 mg/m2) was administered to patients with LMS via 1‐h intravenous (i.v.) infusion on day 1 of every 21‐day (q21d) cycle. Unesbulin dispersible tablets were administered orally twice weekly (b.i.w.), starting on day 2 of every cycle, except for cycle 2 (C2), where unesbulin was dosed either on day 1 together with DTIC or on day 2, 1 day after DTIC administration. The PK of DTIC, AIC, and unesbulin in cycle 1 (C1) and C2 were estimated using noncompartmental analysis. DTIC and AIC were measurable immediately after the start of infusion and reached maximum plasma concentration (Cmax) immediately or shortly after end of infusion at 1.0 and 1.4 h (time to Cmax), respectively. Co‐administration of unesbulin orally at 200 mg or above with DTIC inhibited cytochrome P450 (CYP)1A2‐mediated DTIC metabolism, resulting in 66.7% reduction of AIC exposures. Such inhibition could be mitigated when unesbulin was dosed the day following DTIC infusion. Repeated unesbulin dosing demonstrated evidence of clinical CYP1A2 induction and increased AIC Cmax by 69.4% and area under concentration‐time curve to infinity by 57.9%. No meaningful difference in unesbulin PK was observed between C2 and C1. The combination therapy of 1000 mg/m2 i.v. DTIC q21d and 300 mg unesbulin b.i.w. in a staggered regimen is well‐tolerated in patients with LMS. [ABSTRACT FROM AUTHOR]

As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient's needs. One of the promising tools which have such capacity is 3D printing technology. However, manufacturing small batches of drugs for each patient might lead to huge test burden, including the need to conduct bioequivalence trials of formulations to support the change of equipment or strength. In this paper we demonstrate how to use 3D printing in conjunction with virtual bioequivalence trials based on physiologically based pharmacokinetic (PBPK) modeling. For this purpose, we developed 3D printed ropinirole formulations and tested their bioequivalence with the reference product Polpix. The Simcyp simulator and previously developed ropinirole PBPK model were used for the clinical trial simulations. The Weibull-fitted dissolution profiles of test and reference formulations were used as inputs for the model. The virtual bioequivalence trials were run using parallel design. The study power of 80% was reached using 125 individuals. The study demonstrated how to use PBPK modeling in conjunction with 3D printing to test the virtual bioequivalence of newly developed formulations. This virtual experiment demonstrated the bioequivalence of one of the newly developed formulations with a reference product available on a market. [ABSTRACT FROM AUTHOR]

The aim of this paper was to investigate the effects of formulation parameters on the physicochemical and pharmacokinetic (PK) behavior of amorphous printlets of lopinavir (LPV) manufactured by selective laser sintering 3D printing method (SLS). The formulation variables investigated were disintegrants (magnesium aluminum silicate at 5–10%, microcrystalline cellulose at 10–20%) and the polymer (Kollicoat® IR at 42–57%), while keeping printing parameters constant. Differential scanning calorimetry, X-ray powder diffraction, and Fourier-transform infrared analysis confirmed the transformation of the crystalline drug into an amorphous form. A direct correlation was found between the disintegrant concentration and dissolution. The dissolved drug ranged from 71.1 ± 5.7% to 99.3 ± 2.7% within 120 min. A comparative PK study in rabbits showed significant differences in the rate and extent of absorption between printlets and compressed tablets. The values for Tmax, Cmax, and AUC were 4 times faster, and 2.5 and 1.7 times higher in the printlets compared to the compressed tablets, respectively. In conclusion, the SLS printing method can be used to create an amorphous delivery system through a single continuous process. [ABSTRACT FROM AUTHOR]

Vitamins are crucial for sustaining life because they play an essential role in numerous physiological processes. Vitamin deficiencies can lead to a wide range of severe health issues. In this context, there is a need to administer vitamin supplements through appropriate routes, such as the oral route, to ensure effective treatment. Therefore, understanding the pharmacokinetics of vitamins provides critical insights into absorption, distribution, and metabolism, all of which are essential for achieving the desired pharmacological response. In this review paper, we present information on vitamin deficiencies and emphasize the significance of understanding vitamin pharmacokinetics for improved clinical research. The pharmacokinetics of several vitamins face various challenges, and thus, this work briefly outlines the current issues and their potential solutions. We also discuss the feasibility of enhanced nanocarrier‐based pharmaceutical formulations for delivering vitamins. Recent studies have shown a preference for nanoformulations, which can address major limitations such as stability, solubility, absorption, and toxicity. Ultimately, the pharmacokinetics of pharmaceutical dosage forms containing vitamins can impede the treatment of diseases and disorders related to vitamin deficiency. [ABSTRACT FROM AUTHOR]

This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug. [ABSTRACT FROM AUTHOR]