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Cancer Chemotherapy and Pharmacology Oct 2021High-dose methotrexate (HDMTX) is administered for the treatment of a variety of malignant tumors. Wide intra- and inter-individual variabilities characterize the...
PURPOSE
High-dose methotrexate (HDMTX) is administered for the treatment of a variety of malignant tumors. Wide intra- and inter-individual variabilities characterize the pharmacokinetics of MTX, which is mostly excreted renally. HDMTX dosages are prescribed as a function of body surface area whereas dose adjustments depending on renal function are not well defined. We develop a population pharmacokinetic model with a physiological description of renal excretion as the basis for clinical tools able to suggest model-informed dosages and support therapeutic monitoring.
METHODS
This article presents a minimal physiologically based pharmacokinetic (PBPK) model for HDMTX, which specifically accounts for individual characteristics such as body weight, height, gender, age, hematocrit, and serum creatinine to provide individualized predictions. The model supplies a detailed and mechanistic description of capillary and cellular exchanges between plasma, interstitial fluid, and intracellular fluid compartments, and focuses on an individualized description of renal excretion.
RESULTS
The minimal PBPK model is identified and validated with a literature dataset based on Chinese patients suffering from primary central nervous system lymphoma. A comparison with a pharmacokinetic model from the literature suggests that the proposed model provides improved predictions. Remarkably, the model does not present any significant bias in a wide range of degrees of renal function.
CONCLUSION
Results show that model predictions can capture the wide intra- and inter-individual variability of HDMTX, and highlight the role played by the individual degree of renal function. The proposed model can be the basis for the development of clinical decision-support systems for individualized dosages and therapeutic monitoring.
Topics: Antimetabolites, Antineoplastic; Dose-Response Relationship, Drug; Drug Monitoring; Female; Humans; Kidney; Male; Methotrexate; Models, Biological; Neoplasms
PubMed: 34120234
DOI: 10.1007/s00280-021-04305-2 -
Clinical Pharmacokinetics Aug 2023Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The...
BACKGROUND AND OBJECTIVE
Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations.
OBJECTIVE
We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges.
METHODS
Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges.
RESULTS
Plasma (n = 1973) and whole blood (n = 1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.
CONCLUSION
Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.
Topics: Humans; Tacrolimus; Immunosuppressive Agents; Transplant Recipients; Cohort Studies; Kidney; Lung
PubMed: 37306899
DOI: 10.1007/s40262-023-01259-x -
Toxicology Letters Oct 2017Octamethylcyclotetrasiloxane (D) and decamethylcyclopentasiloxane (D) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates...
Octamethylcyclotetrasiloxane (D) and decamethylcyclopentasiloxane (D) are low molecular weight cyclic volatile methyl siloxanes (cVMSs) primarily used as intermediates or monomers in the production of high molecular weight silicone polymers. The use of D as a direct ingredient in personal care products has declined significantly over the past 20 years, although it may be present as a residual impurity in a variety of consumer products. D is still used as an intentional ingredient in cosmetics, consumer products and in dry cleaning. Persons who may be exposed include occupational exposure for workers, and potential inhalation or dermal exposure for consumers and the general public. Because of the diverse use, especially of D, and the potential for human exposure, a comprehensive program was undertaken to understand the kinetics, metabolism, enzyme induction and toxicity of D and D in rats following relevant routes of exposure. Physiologically based pharmacokinetic (PBPK) models utilizing these studies have been reported for D and D in the rat and human following dermal and inhalation exposures, with the oral uptake component of the model being limited in its description. Data from high dose oral studies in corn oil and simethicone vehicles and neat were used in the D/D harmonized PBPK model development. It was uncertain if the inability to adequately describe the oral uptake was due to unrealistic high doses or unique aspects of the chemistry of D/D Low dose studies were used to provide data to refine the description of oral uptake in the model by exploring the dose dependency and the impact of a more realistic food-like vehicle. Absorption, distribution, metabolism and elimination (ADME) of D and D was determined following a single low oral gavage dose of C-D and C-D at 30 and 100mg/kg body weight (bw), respectively, in a rodent liquid diet. Comparison of the low vs. high dose oral gavage administration of D and D demonstrated dose-dependent kinetic behavior. Data and modeling results suggest differences in metabolism between low and high dose administration indicating high dose administration results in or approaches non-linear saturated metabolism. These low dose data sets were used to refine the D/D multi-route harmonized PBPK model to allow for a better description of the disposition and toxicokinetics of D/D following oral exposure. With a refined oral uptake description, the model could be used in risk assessment to better define the internal dose of D and D following exposure to D and D via multiple routes.
Topics: Adipose Tissue; Administration, Inhalation; Adrenal Glands; Animals; Area Under Curve; Carbon Isotopes; Environmental Pollutants; Female; Gastrointestinal Tract; Liver; Lung; Male; Ovary; Rats; Rats, Inbred F344; Siloxanes; Spleen; Testis; Tissue Distribution; Uterus
PubMed: 28511864
DOI: 10.1016/j.toxlet.2017.05.002 -
CNS Drugs Mar 2014Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5'-diphosphocholine (CDP-choline), which is identical to the natural... (Review)
Review
Citicoline is the generic name of the pharmaceutical substance that chemically is cytidine-5'-diphosphocholine (CDP-choline), which is identical to the natural intracellular precursor of phospholipid phosphatidylcholine. Following injection or ingestion, citicoline is believed to undergo quick hydrolysis and dephosphorylation to yield cytidine and choline, which then enter the brain separately and are used to resynthesize CDP-choline inside brain cells. Neuroprotective activity of citicoline has been repeatedly shown in preclinical models of brain ischaemia and trauma, but two recent, large, pivotal clinical trials have revealed no benefits in ischaemic stroke and traumatic brain injury. However, the substance seems to be beneficial in some slowly advancing neurodegenerative disorders such as glaucoma and mild vascular cognitive impairment. This paper critically discusses issues related to the clinical pharmacology of citicoline, including its pharmacokinetics/biotransformation and pharmacodynamics/mode of action. It is concluded that at present, there is no adequate description of the mechanism(s) of the pharmacological actions of this substance. The possibility should be considered and tested that, in spite of apparently fast catabolism, the intact citicoline molecule or the phosphorylated intermediate products of its hydrolysis, cytidine monophosphate and phosphocholine, are pharmacologically active.
Topics: Animals; Brain; Brain Injuries; Brain Ischemia; Clinical Trials as Topic; Cytidine Diphosphate Choline; Humans; Neurodegenerative Diseases; Neuroprotective Agents; Stroke
PubMed: 24504829
DOI: 10.1007/s40263-014-0144-8 -
British Journal of Pharmacology Sep 2014The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in... (Review)
Review
The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property-distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics.
Topics: Chemistry, Pharmaceutical; Humans; Models, Biological; Nanomedicine; Pharmaceutical Preparations; Pharmacokinetics
PubMed: 24467481
DOI: 10.1111/bph.12604 -
Drug Delivery Dec 2020With the development of nanotechnology, self-assembled chitosan/phospholipid nanoparticles (SACPNs) show great promise in a broad range of applications, including... (Review)
Review
With the development of nanotechnology, self-assembled chitosan/phospholipid nanoparticles (SACPNs) show great promise in a broad range of applications, including therapy, diagnosis, in suit imaging and on-demand drug delivery. Here, a brief review of the SACPNs is presented, and its critical underlying formation mechanisms are interpreted with an emphasis on the intrinsic physicochemical properties. The state-of-art preparation methods of SACPNs are summarized, with particular descriptions about the classic solvent injection method. Then SACPNs microstructures are characterized, revealing the unique spherical core-shell structure and the drug release mechanisms. Afterwards, a comprehensive and in-depth depiction of their emerging applications, with special attention to drug delivery areas, are categorized and reviewed. Finally, conclusions and outlooks on further advancing the SACPNs toward a more powerful and versatile platform for investigations covering from fundamental understanding to developing multi-functional drug delivery systems are discussed.
Topics: Chemistry, Pharmaceutical; Chitosan; Drug Carriers; Drug Liberation; Hydrogen-Ion Concentration; Nanoparticles; Particle Size; Phospholipids
PubMed: 31983258
DOI: 10.1080/10717544.2020.1716878 -
Clinical and Translational Science Aug 2022Pharmacokinetics is the cornerstone of understanding drug absorption, distribution, metabolism, and elimination. It is also the key to describing variability in drug...
Pharmacokinetics is the cornerstone of understanding drug absorption, distribution, metabolism, and elimination. It is also the key to describing variability in drug response caused by drug-drug interactions (DDIs), pharmacogenetics, impaired kidney and liver function, etc. This tutorial aims to provide a guideline and step-by-step tutorial on essential considerations when designing clinical pharmacokinetic studies and reporting results. This includes a comprehensive guide on how to conduct the statistical analysis and a complete code for the statistical software R. As an example, we created a mock dataset simulating a clinical pharmacokinetic DDI study with 12 subjects who were administered 2 mg oral midazolam with and without an inducer of cytochrome P450 3A. We provide a step-by-step guide to the statistical analysis of this clinical pharmacokinetic study, including sample size/power calculation, descriptive statistics, noncompartmental analyses, and hypothesis testing. The different analyses and parameters are described in detail, and we provide a complete R code ready to use in supplementary files. Finally, we discuss important considerations when designing and reporting clinical pharmacokinetic studies. The scope of this tutorial is not limited to DDI studies, and with minor adjustments, it applies to all types of clinical pharmacokinetic studies. This work was done by early career researchers for early career researchers. We hope this tutorial may help early career researchers when getting started on their own pharmacokinetic studies. We encourage you to use this as an inspiration and starting point and continuously evolve your statistical skills.
Topics: Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Humans; Midazolam; Models, Biological
PubMed: 35570335
DOI: 10.1111/cts.13305 -
International Journal of Molecular... Apr 2019Fritillariae Thunbergii Bulbus (FTB) has been widely used as an antitussive herb for thousands of years in China. However, FTB's traditional uses, chemical compounds and... (Review)
Review
Fritillariae Thunbergii Bulbus (FTB) has been widely used as an antitussive herb for thousands of years in China. However, FTB's traditional uses, chemical compounds and pharmacological activities have not been systematically reviewed. This study aimed to review its traditional uses, phytochemistry, pharmacodynamics, pharmacokinetics and toxicity. We searched the Encyclopedia of Traditional Chinese Medicine to explore the historical records which indicate that it acts to clear heat, resolve phlegm, relieve cough, remove toxicity and disperse abscesses and nodules. We searched 11 databases to identify potential phytochemical or pharmacological studies. Characteristics of its chemical constituents, pharmacological effects, pharmacokinetic and toxicity were descriptively summarized. A total of 9706 studies were identified and 83 of them were included. As a result, 134 chemical constituents were identified, including 26 alkaloids, 29 compounds found in essential oils, 13 diterpenoids, two carbohydrates, two sterols, 18 amino acids, six nucleosides, four nucleobases, four fatty acids, three lignans, and 27 elements. Thirteen pharmacological effects of FTB were identified, including anti-cancer, tracheobronchial relaxation, antitussive, expectorant, anti-muscarinic, anti-inflammation, anti-thyroid, regulation of blood rheology, antiulcer, anti-diarrhea, pain suppression, antioxidation and neuroprotection. These pharmacological activities may be mainly attributed to the alkaloids in FTB. Further phytochemical, pharmacological and network pharmacological studies are recommended.
Topics: Animals; Asteraceae; Humans; Phytochemicals; Plant Extracts; Toxicity Tests
PubMed: 30987173
DOI: 10.3390/ijms20071667 -
European Journal of Pharmaceutics and... Aug 2020The oral administration of solid dosage forms is the commonest method to achieve systemic therapy and relies on the drug's solubility in human intestinal fluid (HIF), a...
The oral administration of solid dosage forms is the commonest method to achieve systemic therapy and relies on the drug's solubility in human intestinal fluid (HIF), a key factor that influences bioavailability and biopharmaceutical classification. However, HIF is difficult to obtain and is known to be variable, which has led to the development of a range of simulated intestinal fluid (SIF) systems to determine drug solubility in vitro. In this study we have applied a novel multidimensional approach to analyse and characterise HIF composition using a published data set in both fasted and fed states with a view to refining the existing SIF approaches. The data set provided 152 and 172 measurements of five variables (total bile salt, phospholipid, total free fatty acid, cholesterol and pH) in time-dependent HIF samples from 20 volunteers in the fasted and fed state, respectively. The variable data sets for both fasted state and fed state are complex, do not follow normal distributions but the amphiphilic variable concentrations are correlated. When plotted 2-dimensionally a generally ellipsoid shaped data cloud with a positive slope is revealed with boundaries that enclose published fasted or fed HIF compositions. The data cloud also encloses the majority of fasted state and fed state SIF recipes and illustrates that the structured nature of design of experiment (DoE) approaches does not optimally cover the variable space and may examine media compositions that are not biorelevant. A principal component analysis in either fasted or fed state in combination with fitting an ellipsoid shape to enclose the data results in 8 points that capture over 95% of the compositional variability of HIF. The variable's average rate of concentration change in both fasted state and fed state over a short time scale (10 min) is zero and a Euclidean analysis highlights differences between the fasted and fed states and among individual volunteers. The results indicate that a 9-point DoE (8 + 1 central point) could be applied to investigate drug solubility in vitro and provide statistical solubility limits. In addition, a single point could provide a worst-case solubility measurement to define the lowest biopharmaceutical classification boundary or for use during drug development. This study has provided a novel description of HIF composition. The approach could be expanded in multiple ways by incorporation of further data sets to improve the statistical coverage or to cover specific patient groups (e.g., paediatric). Further development might also be possible to analyse information on the time dependent behaviour of HIF and to guide HIF sampling and analysis protocols.
Topics: Administration, Oral; Body Fluids; Fasting; Humans; Intestinal Absorption; Intestinal Secretions; Intestines; Pharmaceutical Preparations; Phospholipids; Solubility
PubMed: 32585351
DOI: 10.1016/j.ejpb.2020.06.011 -
Drug Metabolism and Disposition: the... Dec 2023The utility of PBPK models in support of drug development has been well documented. During the discovery stage, PBPK has increasingly been applied for early risk...
The utility of PBPK models in support of drug development has been well documented. During the discovery stage, PBPK has increasingly been applied for early risk assessment, prediction of human dose, toxicokinetic dose projection and early formulation assessment. Previous review articles have proposed model building and application strategies for PBPK-based first in human predictions with comprehensive descriptions of the individual components of PBPK models. This includes the generation of decision trees, based on comprehensive literature reviews, to guide the application of PBPK in the discovery setting. The goal of this mini review is to provide additional guidance on the real-world application of PBPK, in support of the discovery stage of drug development. In this mini review, our goal is to provide guidance on the typical steps involved in the development and application of a PBPK model during drug discovery to assist in decision making. We have illustrated our recommended approach through description of case examples, where PBPK has been successfully applied to aid in human PK projection, candidate selection and prediction of drug interaction liability for parent and metabolite. Through these case studies, we have highlighted fundamental issues, including pre-verification in preclinical species, the application of empirical scalars in the prediction of clearance from systems, in silico prediction of permeability and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed. Through description of three case studies, we have highlighted the fundamental principles of PBPK application during drug discovery. These include pre-verification of the model in preclinical species, application of empirical scalars where necessary in the prediction of clearance, in silico prediction of permeability, and the exploration of aqueous and biorelevant solubility data to predict dissolution. In addition, current knowledge gaps have been highlighted and future directions proposed.
PubMed: 38123941
DOI: 10.1124/dmd.122.001036