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Model informed precision dosing for warfarin is to provide individualized dosing by integrating information related to patient characteristics, disease status and pharmacokinetics /pharmacodynamics of warfarin, through mathematical modeling and simulation techniques based on the quantitative pharmacology. Compared with empirical dosing, it can improve the safety, effectiveness, economy, and adherence of pharmacotherapy of warfarin. This consensus report describes the commonly used modeling and simulation techniques for warfarin, their application in developing and adjusting dosing regimens, medication adherence and economy. Moreover, this consensus also elaborates the detailed procedures for the implementation in the warfarin pharmacy service pathway to facilitate the development and application of model informed precision dosing for warfarin.
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AIM: To investigate the absorption of helicid in different segments of intestine based on rat everted intestine sac model. METHODS: To establish a high-performance liquid chromatography method for simultaneous determination of helicid and its metabolite. Krebs-ringer solution containing helicid was added to everted intestine sacs of different segments (duodenum, Jejunum, ileum and colon). Drug concentration in sacs was determined at different time points (5, 10, 15, 30, 45, 60, 75, 90 min). Adsorptions of helicid in four intestinal segments were compared. RESULTS: This high-performance liquid chromatography was successfully applied to the simultaneous determination of helicid and its metabolite. Absorption of helicid was rapid and time-dependent. The absorption and metabolism of helicid in duodenum segment were higher than these in other segments. CONCLUSION: The duodenum segment is the main site of segmental absorption and metabolism of helicid. This is the first report on intestinal segment metabolism of helicid.
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AIM: To study chronopharmacokinetics of helicid and its metabolites. METHODS: An HPLC-MS method for simultaneous determination of helicid and its three phase I metabolites were established and validated. At 8:00, 14:00 and 0:00, the rats were given helicid 50 mg/kg by gavage, respectively. Blood samples were collected from ophthalmic venous plexus. Then plasma concentration was measured. Pharmacokinetic behaviors of the original drug and its metabolites after administration at different time points were calculated and compared. RESULTS: This established HPLC-MS/MS method was successfully applied to simultaneous determination of helicid and its three metabolites in rat plasma after intragastric administration. Using AUC
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Model informed precision dosing (MIPD) is a new concept to guide precision dosing for individual patient by modeling and simulation based on the available information about the individual patient, medications and the disease. Compared to the empirical dosing, MIPD could improve the efficacy, safety, economics and adherence of the pharmacotherapy according to the individual's pathophysiology, genotyping and disease progression. This consensus report provides a brief account of the concept, methodology and implementation of MIPD as well as clinical decision supporting systems for MIPD. The status and future advancing of MIPD was also discussed to facilitate the appropriate application and development of MIPD in China.
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With the increasing cost of drug development and clinical trials, it is of great value to make full use of all kinds of data to improve the efficiency of drug development and to provide valid information for medication guidelines. Model-based meta-analysis (MBMA) combines mathematical models with meta-analysis to integrate information from multiple sources (preclinical and clinical data, etc.) and multiple dimensions (targets/mechanisms, pharmacokinetics/pharmacodynamics, diseases/indications, populations, regimens, biomarkers/efficacy/safety, etc.), which not only provides decision-making for all key points of drug development, but also provides effective information for rational drug use and cost-effectiveness analysis. The classical meta-analysis requires high homogeneity of the data, while MBMA can combine and analyze the heterogeneous data of different doses, different time courses, and different populations through modeling, so as to quantify the dose-effect relationship, time-effect relationship, and the relevant impact factors, and thus the efficacy or safety features at the level of dose, time and covariable that have not been involved in previous studies. Although the modeling and simulation methods of MBMA are similar to population pharmacokinetics/pharmacodynamics (Pop PK/PD), compared with Pop PK/PD, the advantage of MBMA is that it can make full use of literature data, which not only improves the strength of evidence, but also can answer the questions that have not been proved or can not be answered by a single study. At present, MBMA has become one of the important methods in the strategy of model-informed drug development (MIDD). This paper will focus on the application value, data analysis plan, data acquisition and processing, data analysis and reporting of MBMA, in order to provide reference for the application of MBMA in drug development and clinical practice.
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Two-stage designs for the assessment of bioequivalence have been recently accepted in various regulatory authorities.However controlling type Ⅰ error rates around 5％ at targeted power is still a great challenge for applying two-stage method.This paper reviewed the feature of present designs of the two-stage bioequivalence.The decision tree,nominal significance level,and sample size recalculation in previously published methods were also introduced in detail,which would be referential for domestic sponsors in the study of two-stage design bioequivalence.
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Aims To construct an expression vector of human lncRNA H 1 9 ,and to determine the effect of H1 9 overexpression on MCF-7 cell proliferation. Methods Total RNA was extracted from MCF-7 cells,and the full-length of H1 9 lncRNA was amplified by RT-PCR and subcloned into pcDNA3.1 (-)ex-pression vector.The constructed H1 9 expression vector was transfected into HEK-293T and COS-7 cells and the H1 9 lncRNA expression was evaluated by real-time PCR.Following the transfection of H1 9 expression vec-tor into MCF-7 cells for 0,24h and 48h and H1 9 siR-NA interference fragment into MCF-7 cells for 24h, MCF-7 cell proliferation was determined by MTS as-say.Results A hH1 9-pcDNA3.1 (-)expression vector was successfully constructed. At Forty-eight hours after the transfection with H1 9 expression vector in to MCF-7 cells,cell proliferation was significantly increased in the transfected group compared to those without transfection and to those transfected with a neg-ative control vector,while twenty-four hours after the transfection with H1 9 siRNA interference fragment into MCF-7 cells,cell proliferation was significantly de-creased in the transfected group compared to those transfected with a negative control vector.Conclusion Ectopic overexpression of H1 9 lncRNA can promote breast cancer MCF-7 cell proliferation.
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Generic drug products (test products: drug A, B...) are bioequivalent to an innovator product (reference product) when their bioavailabilities in the same molar dose are similar. Bioavailability is usually expressed by following pharmacokinetic parameters: the area under plasma concentration-time curve (AUC), the maximum plasma concentration (Cmax) and the time of maximum plasma concentration (tmax). This paper used a two period crossover bioequivalence study to develop convenient, friendly user interface software, BA&BE Analysis to statistically process data in clinical pharmacology studies and other areas. The method involves user input of data for analysis into a grid format, setting variables and parameters, followed by one-way analysis of variance (ANOVA), bioavailability and bioequivalence analysis of the data. The software developed in the present study should help scientists to carry out data analysis of bioavailability and bioequivalence testing quickly and easily.
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In this review, the author analyzed the challenges in modern research and development of Traditional Chinese Medicine (TCM) products. Chinese traditional and herb drugs have gained interest from the international medical, biomedical and pharmaceutical institutions as potential source of valuable medicinal agents. For the researches and development of TCMs, the first challenge is to evaluate the efficacy, pharmacological properties, action mechanism and active chemical constituents. The second one is to summarize the issues for developing safety research methodologies, to improve the quality and enhance the value of research in TCM and to provide appropriate evaluation methods to facilitate the regulation and registration of TCM products, and the third is to study drug metabolism and pharmacokinetics, and the fourth is to apply new "-omics" techniques and tools in new revolution in drug discovery-development and to impact on modern research of TCM products. This interest is needed to apply modern research on the development and exploration of the promising medical potential resources of Chinese traditional and herbal drugs, especially from medicinal plants.
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NDST(New Drug Statistical Treatment)is a powerful tool for treating data of clinical trial and pre-clinical experimentation in the study of new drug. This paper, combined the some examples, introduced the new edition of the software (NDST-21) on the function and characteristics.
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Many computer systems can be used in the diagnosis and care of subjects in a clinical study,in dispensing drug supplies,and in performing laboratory tests required by the study protocol.It is important that these systems are closely controlled and perform reliably every time they are used.International regulations require that such systems be well documented.Audits and inspections at clinical study sites under Good Clinical Practice(GCP)will check such systems to be sure that they are reliable in performance and that their data is trustworthy.The Principal Investigator in a study is responsible for the quality of all computer systems used to meet the study protocol and for the quality and trustworthiness of all trial data collected either by paper or computer.
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Aim To establish an analytical method for determination of compound G004 concentration in plasma and investigate its application to pharmacokinetics and absolute bioavailability in rats.Methods 5.0 and 2.5 mg?kg~(-1) compound G004 were given via ig and iv respectively to SD rats.Blood samples were collected at various time points after administration.Plasma concentration of compound G004 in rats was determined by LC-ESI-MS.Pharmacokinetic parameters were calculated by DAS program and absolute bioavailability was also calculated.Results The method was linear over the range of 0.02～5 mg?L~(-1)(r~2=0.9995).The recovery of compound G004 in rat plasma was more then 87%.Intra-and inter-day precision,expressed as the relative standard deviation(RSD) was less than 15%.After iv compound G004,the main pharmacokinetic parameters T_(2),CLs,V_d,AUC_((0-∞)) were(1.91?0.65) h,(0.36?0.22) L?h~(-1),(0.78?0.36) L ?kg~(-1),(9.52?3.53) mg?L~(-1)?h~(-1) respectively.The major pharmacokinetic parameters T_(max),C_(max),T_(2),AUC_((0-∞)),MRT_((0-12h)) were 0.83 h,(3.33?0.80) mg?L~(-1),(1.77?0.21) h,(10.04?2.43) mg?L~(-1)?h~(-1) and(2.75?0.31)h after ig compound G004.The absolute bioavailability was 52.69% after correction of dosage.Conclusion The method is sensitive and specific which is applicable to pharmacokinetic analysis of compound G004 in rats.