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Molecules (Basel, Switzerland) Dec 2022Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional... (Review)
Review
Natural medicine has been widely used for clinical treatment and health care in many countries and regions. Additionally, extracting active ingredients from traditional Chinese medicine and other natural plants, defining their chemical structure and pharmacological effects, and screening potential druggable candidates are also uprising directions in new drug research and development. Physiologically based pharmacokinetic (PBPK) modeling is a mathematical modeling technique that simulates the absorption, distribution, metabolism, and elimination of drugs in various tissues and organs in vivo based on physiological and anatomical characteristics and physicochemical properties. PBPK modeling in drug research and development has gradually been recognized by regulatory authorities in recent years, including the U.S. Food and Drug Administration. This review summarizes the general situation and shortcomings of the current research on the pharmacokinetics of natural medicine and introduces the concept and the advantages of the PBPK model in the study of pharmacokinetics of natural medicine. Finally, the pharmacokinetic studies of natural medicine using the PBPK models are summed up, followed by discussions on the applications of PBPK modeling to the enzyme-mediated pharmacokinetic changes, special populations, new drug research and development, and new indication adding for natural medicine. This paper aims to provide a novel strategy for the preclinical research and clinical use of natural medicine.
Topics: Pharmaceutical Preparations; Medicine; Models, Biological; Pharmacokinetics
PubMed: 36557804
DOI: 10.3390/molecules27248670 -
Basic & Clinical Pharmacology &... Jan 2022Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability... (Review)
Review
Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability of anticancer drugs is due to both pharmaceutical limitations and physiological barriers. Pharmacokinetic boosting is a strategy to enhance the oral bioavailability of a therapeutic drug by inhibiting physiological barriers through an intentional drug-drug interaction (DDI). This type of strategy has proven effective across several therapeutic indications including anticancer treatment. Pharmacokinetic boosting could improve anticancer drugs lacking or with otherwise unacceptable oral formulations through logistic, economic, pharmacodynamic and pharmacokinetic benefits. Despite these benefits, pharmacokinetic boosting strategies could result in unintended DDIs and are only likely to benefit a limited number of targets. Highlighting this concern, pharmacokinetic boosting has mixed results depending on the boosted drug. While pharmacokinetic boosting did not significantly improve certain drugs, it has resulted in the commercial approval of boosted oral formulations for other drugs. Pharmacokinetic boosting to improve oral anticancer therapy is an expanding area of research that is likely to improve treatment options for cancer patients.
Topics: Administration, Oral; Antineoplastic Agents; Biological Availability; Drug Interactions; Humans; Neoplasms
PubMed: 34117715
DOI: 10.1111/bcpt.13623 -
British Journal of Clinical Pharmacology Dec 19961. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively... (Review)
Review
1. A high therapeutic ratio for the inhaled route of administration is achieved by delivering doses which achieve a high local concentration in the lung and relatively low levels of systemic absorption. 2. Pharmacokinetic evaluation of drug absorption from the lungs provides an accurate and reproducible method for comparing different inhaler delivery systems, as well as for evaluating bioequivalence of generic drug formulations. 3. The measurement of drug absorption from the lungs may also be applied to assess the effects of inhalation technique on drug delivery in vivo. For example with salbutamol delivered via a large volume spacer, lung bioavailability has been shown to be altered by factors such as the number of actuated puffs, inhalation-actuation delay and washing procedure. 4. Differences in drug delivery to the lungs between dry powder reservoir and pressurised metered-dose aerosol devices translate directly into commensurate differences in clinical efficacy for delivery of both inhaled beta 2-adrenoceptor agonists and corticosteroids. 5. For inhaled corticosteroids, pharmacokinetic evaluation using oral charcoal to obviate alimentary absorption may be applied to quantify the relative gut and lung components of systemic bioavailability. In tandem with information on receptor potency and affinity, drug elimination and distribution, these data may help in part to explain observed differences between different inhaled corticosteroids in terms of their systemic bioactivity profiles. 6. Studies are required to evaluate whether pharmacokinetic evaluation of lung absorption is a suitable way of quantifying delivery of nebulised aminoglycoside antibiotics, as for example in patients with cystic fibrosis. 7. Pharmacokinetic evaluation appears to have an established role in the quantification of drug delivery to the lungs and provides important information which is complimentary to other techniques such as radiolabelled deposition. The next decade of research into pharmacokinetics of established and novel drugs and delivery systems is awaited with keen interest, and will hopefully provide a greater understanding into ways of optimising the benefit-risk ratio for inhaled drugs.
Topics: Administration, Inhalation; Biological Availability; Humans; Lung; Pharmacokinetics
PubMed: 8971424
DOI: 10.1046/j.1365-2125.1996.00493.x -
Journal of Pharmacy & Pharmaceutical... 2021The uniqueness of structure and physiology of the lymphatic system make it challenging to delineate all its contributions in the maintenance of our health. However, in... (Review)
Review
The uniqueness of structure and physiology of the lymphatic system make it challenging to delineate all its contributions in the maintenance of our health. However, in the past two decades, the understanding of the importance of the function of this system has evolved and more appreciation has been drawn to the distinctive role it plays in health and disease. The lymphatic system has been linked to the pathophysiology of numerous ailments including cancer, various metabolic diseases, inflammatory conditions, and infections. Moreover, it has also been revealed that lymphatic targeted formulations can enhance the delivery of drugs through the lymphatic system to the bloodstream, bypassing the hepatic first-pass metabolism if taken orally, thus increasing the bioavailability, and improving the pharmacokinetic and toxicological profiles in general. Engineering lymphotropic preparations requires the understanding of many factors, the most important one being that of the physiological environment which they will encounter. Therefore, in this review, we detail the basic structure of the lymphatic system, then highlight the therapeutic and the pharmacokinetic benefits of drug delivery into the lymphatic system. The criteria for drugs and formulations used for lymphotropic delivery are also detailed with a contemporary overview of various studies undertaken in this field.
Topics: Biological Availability; Drug Delivery Systems; Humans; Lymph Nodes; Lymphatic System; Pharmacokinetics
PubMed: 34694988
DOI: 10.18433/jpps32222 -
Pharmaceutical Biology Dec 2021Laurolitsine is an aporphine alkaloid and exhibits potent antihyperglycemic and antihyperlipidemic effects in ob/ob mice.
CONTEXT
Laurolitsine is an aporphine alkaloid and exhibits potent antihyperglycemic and antihyperlipidemic effects in ob/ob mice.
OBJECTIVE
To investigate the pharmacokinetics, tissue distribution and excretion of laurolitsine.
MATERIALS AND METHODS
A LC-MS/MS method was established and validated to determine laurolitsine concentrations in the biological matrix of rats (plasma, tissue homogenate, urine and faeces). 10 Sprague-Dawley (SD) rats were used for plasma exposure study: 5 rats were injected with 2.0 mg/kg of laurolitsine via the tail vein, and the other 5 rats were administered laurolitsine (10.0 mg/kg) by gavage. 25 SD rats used for tissue distribution study and 5 SD rats for urine and faeces excretion study: rats administered laurolitsine (10.0 mg/kg) by gavage. After administered, serial blood, tissue, urine and faeces were collected. Analytical quantification was performed by a previous LC-MS/MS method. The pharmacokinetics, bioavailability, tissue distribution and excretion of laurolitsine were described.
RESULTS
The pharmacokinetic parameters of oral and intravenous administration with were 0.47 and 0.083 h, were 3.73 and 1.67 h, respectively. Oral bioavailability was as low as 18.17%. Laurolitsine was found at a high concentration in the gastrointestinal tract, liver, lungs and kidneys (26 015.33, 905.12, 442.32 and 214.99 ng/g at 0.5 h, respectively) and low excretion to parent laurolitsine in urine and faeces (0.03 and 1.20% in 36 h, respectively).
CONCLUSIONS
This study established a simple, rapid and accurate LC-MS/MS method to determine laurolitsine in different rat samples and successful application in a pharmacokinetic study.
Topics: Administration, Oral; Animals; Aporphines; Biological Availability; Chromatography, Liquid; Half-Life; Litsea; Male; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tissue Distribution
PubMed: 34219593
DOI: 10.1080/13880209.2021.1944221 -
British Journal of Clinical Pharmacology Dec 2015Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations... (Review)
Review
Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.
Topics: Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP1A2; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Humans; Infant, Newborn; Models, Biological; Pharmacokinetics; Tissue Distribution
PubMed: 26256466
DOI: 10.1111/bcp.12741 -
Advanced Drug Delivery Reviews Jun 2015Although significant progress has been made in experimental high throughput screening (HTS) of ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic... (Review)
Review
Although significant progress has been made in experimental high throughput screening (HTS) of ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic properties, the ADME and Toxicity (ADME-Tox) in silico modeling is still indispensable in drug discovery as it can guide us to wisely select drug candidates prior to expensive ADME screenings and clinical trials. Compared to other ADME-Tox properties, human oral bioavailability (HOBA) is particularly important but extremely difficult to predict. In this paper, the advances in human oral bioavailability modeling will be reviewed. Moreover, our deep insight on how to construct more accurate and reliable HOBA QSAR and classification models will also discussed.
Topics: Administration, Oral; Animals; Biological Availability; Computer Simulation; Humans; Models, Biological; Pharmacokinetics
PubMed: 25582307
DOI: 10.1016/j.addr.2015.01.001 -
CPT: Pharmacometrics & Systems... Dec 2022The gold-standard approach for modeling pharmacokinetic mediated drug-drug interactions is the use of physiologically-based pharmacokinetic modeling and population... (Review)
Review
The gold-standard approach for modeling pharmacokinetic mediated drug-drug interactions is the use of physiologically-based pharmacokinetic modeling and population pharmacokinetics. However, these models require extensive amounts of drug-specific data generated from a wide variety of in vitro and in vivo models, which are later refined with clinical data and system-specific parameters. Machine learning has the potential to be utilized for the prediction of drug-drug interactions much earlier in the drug discovery cycle, using inputs derived from, among others, chemical structure. This could lead to refined chemical designs in early drug discovery. Machine-learning models have many advantages, such as the capacity to automate learning (increasing the speed and scalability of predictions), improved generalizability by learning from multicase historical data, and highlighting statistical and potentially clinically significant relationships between input variables. In contrast, the routinely used mechanistic models (physiologically-based pharmacokinetic models and population pharmacokinetics) are currently considered more interpretable, reliable, and require a smaller sample size of data, although insights differ on a case-by-case basis. Therefore, they may be appropriate for later stages of drug-drug interaction assessment when more in vivo and clinical data are available. A combined approach of using mechanistic models to highlight features that can be used for training machine-learning models may also be exploitable in the future to improve the performance of machine learning. In this review, we provide concepts, strategic considerations, and compare machine learning to mechanistic modeling for drug-drug interaction risk assessment across the stages of drug discovery and development.
Topics: Humans; Models, Biological; Drug Interactions; Machine Learning; Drug Discovery; Pharmacokinetics
PubMed: 36176050
DOI: 10.1002/psp4.12870 -
British Journal of Clinical Pharmacology Feb 2022This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing...
AIMS
This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing regimens.
METHODS
A PBPK model of imatinib was built in the Simcyp Simulator (version 17) integrating in vitro drug metabolism and clinical pharmacokinetic data. The model accounts for ethnic differences in body size and abundance of drug-metabolising enzymes and proteins involved in imatinib disposition. Utility of this model for prediction of imatinib pharmacokinetics was evaluated across different dosing regimens and ethnic groups. The impact of ethnicity on imatinib dosing was then assessed based on the established range of trough concentrations (C ).
RESULTS
The PBPK model of imatinib demonstrated excellent predictive performance in describing pharmacokinetics and the attained C in patients from different ethnic groups, shown by prediction differences that were within 1.25-fold of the clinically-reported values in published studies. PBPK simulation suggested a similar dose of imatinib (400-600 mg/d) to achieve the desirable range of C (1000-3200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulation indicated that patients of African ancestry may benefit from a higher initial dose (600-800 mg/d) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups; however, the clinical data to support this are currently limited.
CONCLUSION
PBPK simulations highlighted a potential ethnic difference in the recommended initial dose of imatinib between populations of European and African ancestry, but not populations of Chinese and Japanese ancestry.
Topics: Asian People; Computer Simulation; Humans; Imatinib Mesylate; Metabolic Clearance Rate; Models, Biological; Pharmacokinetics
PubMed: 34535920
DOI: 10.1111/bcp.15084 -
Advanced Drug Delivery Reviews Dec 2020Despite the increasing trend towards subcutaneous delivery of monoclonal antibodies, factors influencing the subcutaneous bioavailability of these molecules remain... (Review)
Review
Despite the increasing trend towards subcutaneous delivery of monoclonal antibodies, factors influencing the subcutaneous bioavailability of these molecules remain poorly understood. To address critical knowledge gaps and issues during development of subcutaneous dosage forms for monoclonal antibodies, the Subcutaneous Drug Delivery and Development Consortium was convened in 2018 as a pre-competitive collaboration of recognized industry experts. One of the Consortium's eight problem statements highlights the challenges of predicting human bioavailability of subcutaneously administered monoclonal antibodies due to a lack of reliable in vitro and preclinical in vivo predictive models. In this paper, we assess the current landscape in subcutaneous bioavailability prediction for monoclonal antibodies and discuss the gaps and opportunities associated with bioavailability models for biotherapeutics. We also issue an open challenge to industry and academia, encouraging the development of reliable models to enable subcutaneous bioavailability prediction of therapeutic large molecules in humans and improve translation from preclinical species.
Topics: Antibodies, Monoclonal; Area Under Curve; Biological Availability; Biological Products; Dose-Response Relationship, Drug; Drug Delivery Systems; Drug Liberation; Humans; Hydrogen-Ion Concentration; Injections, Subcutaneous; Models, Biological; Solubility
PubMed: 32473188
DOI: 10.1016/j.addr.2020.05.009