To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract （PPE）...To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract （PPE） and oral administration of PPE and three types of decoctions in Guanxin Ⅱ prescription, respectively, were determined by HPLC analyses. NONMEM （nonlinear mixed-effect modeling） method was used to analyze full set of pharmacokinetic data directly. A two-compartment model with first-order degradation in absorption compartment was employed for the data analysis. The mean of population parameters, CL1, V1, CL2, V2, Ka0, and Kal, were measured to be 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135/h, and 0.0135/h, respectively. Inter-individual variabilities were estimated and dose formulation （DF） was identified as a significant covariate of Ka 1, Ka0, and V1. It is concluded that the pharmacokinetic behaviors of paeoniflorin in rats can alter with different dose formulations.展开更多
Aim To investigate the population pharmacokinetics of propofol administered by TCI in Chinese elderly patients. Methods Thirty-two patients with ASA Ⅰ - Ⅱ , 65 - 82 years old, undergoing selective lower abdominal op...Aim To investigate the population pharmacokinetics of propofol administered by TCI in Chinese elderly patients. Methods Thirty-two patients with ASA Ⅰ - Ⅱ , 65 - 82 years old, undergoing selective lower abdominal operation were studied. Propofol was administered by target-controlled infusion with Marsh parameter. The target plasma concentration was 3 μg＇ mL^-1. Radial arterial blood samples were collected and analyzed by reversed phase HPLC with fluorescence detection. Population pharmacokinetic modeling was performed using NONMEM. Inter-individual variability and intra-individual variability of propofol were estimated for clearances and volumes of distribution. The effects of age, body weight, lean body mass, gender, height, hemoglobin, total protein, albumin, creatinine, alanine aminotrans ferase （ALT）, and aspartate aminotransferase （AST） were investigated. The effects of coadministered opioid drugs were also studied. Results The pharmacokinetics of propofol in the Chinese elderly patients was best described by a three-compartment open model. Lean body mass was found to be a covariate for system clearance at significant level （ P 〈 0.005）. The clearance decreased linearly with age as well （ P 〈 0. 005）. The apparent volume of distribution for deep peripheral compartment （V3） was influenced by gender. Elderly female patients showed a higher value for V3. Conclusion The pharmacokinetics of propofol administered by TCI in Chinese elderly patients can be well described by a three-compartment open model. Inclusion of age, lean body mass and gender as covariates significantly improved the model. To ensure the accuracy and precision of target-controlled infusion, the population pharmacokinetic model applied to the individual patient should be adjusted reasonably.展开更多
Population pharmacokinetic meta-analysis method was used in order to obtain the pharmacokinetic characteristics of risperidone and its active metabolite. Eighteen studies were selected from published papers from 1995 ...Population pharmacokinetic meta-analysis method was used in order to obtain the pharmacokinetic characteristics of risperidone and its active metabolite. Eighteen studies were selected from published papers from 1995 to 2011. A model consisted of two compartments for parent drug and one compartment for its active metabolite combined with a flexible absorption process was developed based on the meta-dataset. The population-predicted apparent clearance for risperidone and 9-hydroxyrisperidone, the active metabolite was 7.66 L/h and 7.38 L/h, and the apparent volume of distribution in the central compartment was 70.6 L and 117 L, respectively. The final model was evaluated by visual predictive check（VPC） based on 1000 times model simulation. This model was adequately used to predict clinical therapeutic drug monitoring（TDM） data from 42 Chinese inpatients. Bias（mean prediction errors, MPE） and precision（root mean squared prediction errors, RMSE） were calculated to statistically analysis the population prediction error. It was demonstrated that the model developed from the meta-dataset was reliable and can be used to facilitate the individualized treatment for a target population.展开更多
This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate(STS) in healthy volunteers and coronary heart disease(CHD) patients in order to identify significant covariates for the pharm...This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate(STS) in healthy volunteers and coronary heart disease(CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance(CL) of STS in CHD patients with total bilirubin(TBIL) level of 10 μmol×L^(–1) was 48.7 L×h^(–1) with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L×h^(–1). Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.展开更多
Background：High-dose methotrexate （HD-MTX） with folinic acid （leucovorin） rescue is the gold standard therapy in the treatment of osteosarcoma.The plasma concentration of MTX is closely related to efficacy and to...Background：High-dose methotrexate （HD-MTX） with folinic acid （leucovorin） rescue is the gold standard therapy in the treatment of osteosarcoma.The plasma concentration of MTX is closely related to efficacy and toxicity.There are large individual differences.Many authors have described the pharmacokinetic （PK） profile of MTX regarding osteosarcoma under a variety of circumstances.However,no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models （NONMEM） have been previously reported.The goals of this study were to establish the population pharmacokinetics （PPK） of HD-MTX treatment in Chinese osteosarcoma patients,and to explore the influence of patient covariates and between-occasion variability on drug disposition.Methods：An intravenous HD-MTX solution （10 g/m2） was given 274 times to 148 osteosarcoma patients.MTX plasma concentrations were measured at 0,6,12,24,48 and 72 h after commencement of the infusion,and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations.The PPK model and parameters were estimated using NONMEM software.The effects of fixed-effect factors were evaluated,and the final regression model was obtained.Results：The following population parameters were obtained using a two-compartment model：CL1 （clearance of central compartment）：（CL1）i =CL1 Tv × [1-θCt-MTXNUM × MTXNUM] × [1-θCL1-CrCl1 × （CrCl1-1.89）] × e^ηCLi （L/h）.V1 （central volume）：（V11）i =V1TV × e^ηV1i （L）.CL2 （clearance of peripheral compartment）：（CL2）i =CL2TV × [1-θCL2-BODYAREA × （bodyarea-1.62）] × e^ηCL2i （L/h）.V2 （peripheral compartment）：（V2）i =V2Tv × [1-θV2-bodyarea × （bodyarea-1.62）] × e^ηV2i （L）.The PPK parameters （RSD%） were CL1,V1,CL2 and V2 with values of 6.20 L/h （8.48%）,19.6 L （extremely small）,0.0172 L/h （50.9%） and 0.515 L （39.1%）,respectively.Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL 1,and body surface area had a significant effect on the CL2 and the V2 （P 〈 0.01）.Conclusions：A good fit was derived for the PPK.The model could be used to provide guidance for MTX treatment and reduce adverse effects.展开更多
Objective： To evaluate the effect of covariates on the pharmacokinetic profiles of naringin in the total flavonoids of Drynaria fortunei （Kunze） J. Sin. in the Qianggu Capsule （强骨胶囊） by evaluating Chinese wom...Objective： To evaluate the effect of covariates on the pharmacokinetic profiles of naringin in the total flavonoids of Drynaria fortunei （Kunze） J. Sin. in the Qianggu Capsule （强骨胶囊） by evaluating Chinese women with primary osteoporosis. Methods： A total of 98 female patients from the communities of Jingshan, Beixinqiao, Jiaodaokou, Chaoyangmen, and Donghuamen in Beijing, China, aged 40 to 80 years, were included in this study. Blood samples were collected before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after a single oral dose of Qianggu Capsule. The concentration in blood samples from 32 patients before and 0.5, 1, 2, 3, and 4 h after drug administration were determined by liquid chromatography-tandem mass spectrometry （LC-MS/MS） method, and full set of pharmacokinetic data was analyzed with nonlinear mixed-effect modeling （NONMEM） software. The mean of population parameters clearance （C1）, central distribution volume （V）, absorption rate constant （Kal）, inter-compartmental clearance （C2）, peripheral distribution volume （V2） were set as parameters and estimated through base model, covariate model, and final model. Age, height, weight, blood urea nitrogen （BUN）, serum creatinine （Scr）, alanine transaminase （ALT）, aspartate transaminase （AST）, hyperlipidemia, Liver （Gan） Kidney （Shen） yin insufficiency （GSYI）, Kidney （Shen） yang insufficiency （SYI） were set as covariates. Results： The relationships between these parameters and covariates were analyzed. The results showed that C1 was the main parameter influenced by the selected covariates among the population parameters, and the relationships between the covariates and C1 were analyzed, among the selected covariates hyperlipidemia was identified as significant covariate of C1. Conclusion： The pharmacokinetic behaviors of naringin are altered with hyperlipidemia in Chinese women with primary osteoporosis.展开更多
In the present study, we aimed to develop a population pharmacokinetics(PPK) model of vancomycin(VCM) and propose the individualised dosage regimen for Chinese elderly patients. The data were collected prospectively f...In the present study, we aimed to develop a population pharmacokinetics(PPK) model of vancomycin(VCM) and propose the individualised dosage regimen for Chinese elderly patients. The data were collected prospectively from Chinese elderly patients receiving VCM therapy. Steady-state trough concentrations of VCM were determined using an enzyme-multiplied immunoassay. Patients’ sex, age, body weight, concomitant medications, infection type, and laboratory findings were recorded. The PPK model was developed using nonlinear mixed-effects model software. Moreover, we used Monte Carlo simulations to develop an initial dosage regimen targeting various VCM through concentration ranges based on the final model. We found that VCM clearance(CL) was significantly influenced by post-craniotomy meningitis(PCM) and glomerular filtration rate in elderly patients. Additionally, a new dosage regimen was proposed to individualise VCM regimen for PCM and non-PCM elderly patients. A PPK model was established to estimate the individual VCM CL for elderly patients, which could be applied for individualising doses in the target population.展开更多
Although many population pharmacokinetics（PPK） researches have been conducted on chemical drugs,few have been in the field of Chinese medicine（CM）.Each ingredient in CMs possesses different pharmacokinetic charact...Although many population pharmacokinetics（PPK） researches have been conducted on chemical drugs,few have been in the field of Chinese medicine（CM）.Each ingredient in CMs possesses different pharmacokinetic characteristics,therefore,it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations.To develop an expert consensus on study design and implementation for PPK of CM,in August 2013,6 experts in the field of PPK,CMs pharmacology,and statistics discussed problems on the PPK research protocol of CMs,and a consensus was reached.The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected.The compositions with definite therapeutic effects were selected as indices,and specific time points and sample sizes were designed according to standard PPK design methods.Target components were tested through various chromatography methods.Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs（which assists in reasonable adjustments on clinical dosage）.This consensus specifies the study design and implementation process of PPK.It provides guidance for the following：post-marketing clinical studies,in vivo investigations related to the metabolism in different populations,and development and clinical adjustment of dosages of CMs.展开更多
Objective To study the population pharmacokinetic(PPK)profiles of linezolid in Chinese healthy volunteers and infected patients.Methods Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single ...Objective To study the population pharmacokinetic(PPK)profiles of linezolid in Chinese healthy volunteers and infected patients.Methods Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least5 doses.High performance liquid chromatography was applied to determine the plasma concentration of linezol-展开更多
To investigate pharmacokinetics ofbaicalin after an oral administration of different Shuang-Huang-Lian （SHL） formulations to rats. Different SIlL formulations were orally administered to rats. The concentrations of ...To investigate pharmacokinetics ofbaicalin after an oral administration of different Shuang-Huang-Lian （SHL） formulations to rats. Different SIlL formulations were orally administered to rats. The concentrations of baicalin in rat plasma were determined by HPLC, the non-compartmental pharmacokinetic parameters and population pharmacokinetic parameters of baicalin were estimated by WinNonlin and NONMEM. The plasma concentration profiles of baicalin demonstrated double-peak phenomenon except for group microemulsion prescription 2. Population pharmacokinetic model developed includes four covariates, which were the effect of formulation （FORM） on CL/F and V/F, the effect of body weight （BW） on Ka, and the effect of gender （GEND） on V/F. Numbers 1 to 6 denote SHL formulation decoction, oral liquid, colloidal solution, microemulsion prescription 1, microemulsion prescription 2 and granule, respectively. The equations for the parameters are as following： CL/F = （0.432 ＋ 0.529）. e^ηCl L/h if formulation was 2 or 6, otherwise CL/F = 0.432. e^ηCl L/h ; V/F = （11.3- 4.03 - 3.87. GEND）. e^ηv L if formulation was 5, otherwise V/F = （11.3 - 3.87. GEND）. e^ηv L ; Ka = 0.475. [1 - 0.0223. （BW - 195.1）]. e^ηKah^-1. SHL formulations have significant effects on the nharmacokinefic narameters.展开更多
Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using ...Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using a one-compartment open model with the first order absorption to determine PK parameter estimates with different sampling strategies as a validation of the method. The estimated parameters were further verified by comparing to the observed values. Results The samples collected at the single time point close to the non-informative sampling time point designed by this method led to bias and inaccurate parameter estimations. Furthermore, the relationship between the estimated non-informative sampling time points and the values of the parameter was examined. The non-informative sampling time points have been developed under some typical occasions and the results were plotted to show the tendency. As a result, one non-informative time point was demonstrated to be appropriate for clearance and two for both volume of distribution and constant of absorption in the present study. It was found that the estimates of the non-informative sampling time points developed in the method increase with increases of volume of distribution and the decrease of clearance and constant of absorption. Conclusion A rational sampling strategy during therapeutic drug monitoring can be established using the method present in the study.展开更多
Caffeine is a commonly ingested psychoactive substance which affects alertness and cognition. A clinical study was conducted to determine the effect of orally ingested caffeine on visual analogue scale (VAS) responses...Caffeine is a commonly ingested psychoactive substance which affects alertness and cognition. A clinical study was conducted to determine the effect of orally ingested caffeine on visual analogue scale (VAS) responses in healthy, moderate caffeine-consuming volunteers through the use of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Twelve subjects were recruited for a three-period cross-over study which utilized caffeine containing beverages. Each visit included 8-hour blood plasma and VAS response collection for PK and PD assessment respectively. The VAS used in the study, also called the caffeine analog scale, has been previously validated for caffeine. Population PK-PD modeling was conducted with NONMEM 7.2. Simultaneous and sequential modeling of PK-PD was attempted. Final model selection was based on parameter estimate precision, diagnostic plots, and visual predictive check (VPC) plots. Results showed that a one-compartment open model with first-order absorption and elimination best described the pharmacokinetics of caffeine. Sequential PK-PD modeling was successful and an effect compartment model with linear slope and baseline parameter best described caffeine pharmacodynamics. Diagnostic plots showed no major bias and VPC plots showed agreement between observations and predictions. The model was able to link VAS responses to caffeine concentration in healthy volunteers and may be useful in clinical trial simulations and design.展开更多
The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding ...The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding a stochastic term to the state equation. Compared with the ODEs, the SDEs can model correlated residuals which are ubiquitous in actual pharmacokinetic problems. The Bayesian estimation is provided for nonlinear mixed-effects models based on stochastic differential equations. Combining the Gibbs and the Metropolis-Hastings algorithms, the population and individual parameter values are given through the parameter posterior predictive distributions. The analysis and simulation results show that the performance of the Bayesian estimation for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for population pharmacokinetic data.展开更多
The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. ...The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects （including Han, Mongolian, Korean, Hui and Uigur） using nonlinear mixed-effect modeling （NONMEM）. From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokinetic parameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume Vj of losartan and also has a significant effect on the transit rate （Kt）. A total of 925 out of 1000 iterations succeeded in minimization. The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.展开更多
A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatit...A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatitis C.A model-based meta-analysis of ledipasvir and GS331007,the primary metabolite of sofosbuvir,enabled the integration of pharmacokinetic（PK） information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs.A systematic publication search was conducted for the clinical studies of ledipasvir and sofosbuvir.A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling.A two-compartment disposition model was used for both ledipasvir and GS331007.Zero-order absorption was applied for ledipasvir PK modeling,and a combined zero- and first-order absorption was used for the modeling of GS331007.Absorption lag was observed in concentration-time profiles of both ledipasvir and GS331007.To aid the development of direct-acting antiviral drugs,our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.展开更多
基金National Natural Science Foundation (Grant No. 30472165)
文摘To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract （PPE） and oral administration of PPE and three types of decoctions in Guanxin Ⅱ prescription, respectively, were determined by HPLC analyses. NONMEM （nonlinear mixed-effect modeling） method was used to analyze full set of pharmacokinetic data directly. A two-compartment model with first-order degradation in absorption compartment was employed for the data analysis. The mean of population parameters, CL1, V1, CL2, V2, Ka0, and Kal, were measured to be 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135/h, and 0.0135/h, respectively. Inter-individual variabilities were estimated and dose formulation （DF） was identified as a significant covariate of Ka 1, Ka0, and V1. It is concluded that the pharmacokinetic behaviors of paeoniflorin in rats can alter with different dose formulations.
文摘Aim To investigate the population pharmacokinetics of propofol administered by TCI in Chinese elderly patients. Methods Thirty-two patients with ASA Ⅰ - Ⅱ , 65 - 82 years old, undergoing selective lower abdominal operation were studied. Propofol was administered by target-controlled infusion with Marsh parameter. The target plasma concentration was 3 μg＇ mL^-1. Radial arterial blood samples were collected and analyzed by reversed phase HPLC with fluorescence detection. Population pharmacokinetic modeling was performed using NONMEM. Inter-individual variability and intra-individual variability of propofol were estimated for clearances and volumes of distribution. The effects of age, body weight, lean body mass, gender, height, hemoglobin, total protein, albumin, creatinine, alanine aminotrans ferase （ALT）, and aspartate aminotransferase （AST） were investigated. The effects of coadministered opioid drugs were also studied. Results The pharmacokinetics of propofol in the Chinese elderly patients was best described by a three-compartment open model. Lean body mass was found to be a covariate for system clearance at significant level （ P 〈 0.005）. The clearance decreased linearly with age as well （ P 〈 0. 005）. The apparent volume of distribution for deep peripheral compartment （V3） was influenced by gender. Elderly female patients showed a higher value for V3. Conclusion The pharmacokinetics of propofol administered by TCI in Chinese elderly patients can be well described by a three-compartment open model. Inclusion of age, lean body mass and gender as covariates significantly improved the model. To ensure the accuracy and precision of target-controlled infusion, the population pharmacokinetic model applied to the individual patient should be adjusted reasonably.
基金Guangzhou Municipality Medical and Technology Project(Grant No.20131A011087)Beijing Key Lab of Diagnostics and Therapeutics for Psychiatric disorders 2013 Open Foundation(Grant No.2013JSJB01)Beijing Municipal Education Commission Science and Technology Development Program(Grant No.KM201110025025)
文摘Population pharmacokinetic meta-analysis method was used in order to obtain the pharmacokinetic characteristics of risperidone and its active metabolite. Eighteen studies were selected from published papers from 1995 to 2011. A model consisted of two compartments for parent drug and one compartment for its active metabolite combined with a flexible absorption process was developed based on the meta-dataset. The population-predicted apparent clearance for risperidone and 9-hydroxyrisperidone, the active metabolite was 7.66 L/h and 7.38 L/h, and the apparent volume of distribution in the central compartment was 70.6 L and 117 L, respectively. The final model was evaluated by visual predictive check（VPC） based on 1000 times model simulation. This model was adequately used to predict clinical therapeutic drug monitoring（TDM） data from 42 Chinese inpatients. Bias（mean prediction errors, MPE） and precision（root mean squared prediction errors, RMSE） were calculated to statistically analysis the population prediction error. It was demonstrated that the model developed from the meta-dataset was reliable and can be used to facilitate the individualized treatment for a target population.
基金supported by the Science and Technology Commission of Shanghai Municipality(12DZ1930300,12DZ1930302,12DZ1930303)the Weak Discipline Construction Project(No.2016ZB0301–01)the 2016 Key Clinical Program of Clinical Pharmacy of Shanghai Municipal Commission of Health and Family Planning.cdh3
文摘This study developed a population pharmacokinetic model for sodium tanshinone IIA sulfonate(STS) in healthy volunteers and coronary heart disease(CHD) patients in order to identify significant covariates for the pharmacokinetics of STS. Blood samples were obtained by intense sampling approach from 10 healthy volunteers and sparse sampling from 25 CHD patients, and a population pharmacokinetic analysis was performed by nonlinear mixed-effect modeling. The final model was evaluated by bootstrap and visual predictive check. A total of 230 plasma concentrations were included, 137 from healthy volunteers and 93 from CHD patients. It was a two-compartment model with first-order elimination. The typical value of the apparent clearance(CL) of STS in CHD patients with total bilirubin(TBIL) level of 10 μmol×L^(–1) was 48.7 L×h^(–1) with inter individual variability of 27.4%, whereas that in healthy volunteers with the same TBIL level was 63.1 L×h^(–1). Residual variability was described by a proportional error model and estimated at 5.2%. The CL of STS in CHD patients was lower than that in healthy volunteers and decreased when TBIL levels increased. The bootstrap and visual predictive check confirmed the stability and validity of the final model. These results suggested that STS dosage adjustment might be considered based on TBIL levels in CHD patients.
文摘Background：High-dose methotrexate （HD-MTX） with folinic acid （leucovorin） rescue is the gold standard therapy in the treatment of osteosarcoma.The plasma concentration of MTX is closely related to efficacy and toxicity.There are large individual differences.Many authors have described the pharmacokinetic （PK） profile of MTX regarding osteosarcoma under a variety of circumstances.However,no data concerning Chinese osteosarcoma patient PKs using the nonlinear mixed effects models （NONMEM） have been previously reported.The goals of this study were to establish the population pharmacokinetics （PPK） of HD-MTX treatment in Chinese osteosarcoma patients,and to explore the influence of patient covariates and between-occasion variability on drug disposition.Methods：An intravenous HD-MTX solution （10 g/m2） was given 274 times to 148 osteosarcoma patients.MTX plasma concentrations were measured at 0,6,12,24,48 and 72 h after commencement of the infusion,and the fluorescence polarization immunoassay was used to determine MTX plasma concentrations.The PPK model and parameters were estimated using NONMEM software.The effects of fixed-effect factors were evaluated,and the final regression model was obtained.Results：The following population parameters were obtained using a two-compartment model：CL1 （clearance of central compartment）：（CL1）i =CL1 Tv × [1-θCt-MTXNUM × MTXNUM] × [1-θCL1-CrCl1 × （CrCl1-1.89）] × e^ηCLi （L/h）.V1 （central volume）：（V11）i =V1TV × e^ηV1i （L）.CL2 （clearance of peripheral compartment）：（CL2）i =CL2TV × [1-θCL2-BODYAREA × （bodyarea-1.62）] × e^ηCL2i （L/h）.V2 （peripheral compartment）：（V2）i =V2Tv × [1-θV2-bodyarea × （bodyarea-1.62）] × e^ηV2i （L）.The PPK parameters （RSD%） were CL1,V1,CL2 and V2 with values of 6.20 L/h （8.48%）,19.6 L （extremely small）,0.0172 L/h （50.9%） and 0.515 L （39.1%）,respectively.Creatinine clearance and the number of methotrexate chemotherapy cycles before MTX infusion had a significant effect on the CL 1,and body surface area had a significant effect on the CL2 and the V2 （P 〈 0.01）.Conclusions：A good fit was derived for the PPK.The model could be used to provide guidance for MTX treatment and reduce adverse effects.
基金Supported by Significant Drug Research and Development in Important State Science and Technology Specific and Key Technique Research(No.2009ZX09502-030)
文摘Objective： To evaluate the effect of covariates on the pharmacokinetic profiles of naringin in the total flavonoids of Drynaria fortunei （Kunze） J. Sin. in the Qianggu Capsule （强骨胶囊） by evaluating Chinese women with primary osteoporosis. Methods： A total of 98 female patients from the communities of Jingshan, Beixinqiao, Jiaodaokou, Chaoyangmen, and Donghuamen in Beijing, China, aged 40 to 80 years, were included in this study. Blood samples were collected before and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h after a single oral dose of Qianggu Capsule. The concentration in blood samples from 32 patients before and 0.5, 1, 2, 3, and 4 h after drug administration were determined by liquid chromatography-tandem mass spectrometry （LC-MS/MS） method, and full set of pharmacokinetic data was analyzed with nonlinear mixed-effect modeling （NONMEM） software. The mean of population parameters clearance （C1）, central distribution volume （V）, absorption rate constant （Kal）, inter-compartmental clearance （C2）, peripheral distribution volume （V2） were set as parameters and estimated through base model, covariate model, and final model. Age, height, weight, blood urea nitrogen （BUN）, serum creatinine （Scr）, alanine transaminase （ALT）, aspartate transaminase （AST）, hyperlipidemia, Liver （Gan） Kidney （Shen） yin insufficiency （GSYI）, Kidney （Shen） yang insufficiency （SYI） were set as covariates. Results： The relationships between these parameters and covariates were analyzed. The results showed that C1 was the main parameter influenced by the selected covariates among the population parameters, and the relationships between the covariates and C1 were analyzed, among the selected covariates hyperlipidemia was identified as significant covariate of C1. Conclusion： The pharmacokinetic behaviors of naringin are altered with hyperlipidemia in Chinese women with primary osteoporosis.
基金Guidance Project of Fujian Science and Technology Department(Grant No.2017Y0033)Fujian Medical Innovation Project(Grant No.2017-CX-31)+1 种基金Sail Project of Fujian Medical University(Grant No.2017XQ1068)“Weak Discipline Construction Project” of Shanghai Municipal Commission of Health and Family Planning(Grant No.2016ZB0301-01).
文摘In the present study, we aimed to develop a population pharmacokinetics(PPK) model of vancomycin(VCM) and propose the individualised dosage regimen for Chinese elderly patients. The data were collected prospectively from Chinese elderly patients receiving VCM therapy. Steady-state trough concentrations of VCM were determined using an enzyme-multiplied immunoassay. Patients’ sex, age, body weight, concomitant medications, infection type, and laboratory findings were recorded. The PPK model was developed using nonlinear mixed-effects model software. Moreover, we used Monte Carlo simulations to develop an initial dosage regimen targeting various VCM through concentration ranges based on the final model. We found that VCM clearance(CL) was significantly influenced by post-craniotomy meningitis(PCM) and glomerular filtration rate in elderly patients. Additionally, a new dosage regimen was proposed to individualise VCM regimen for PCM and non-PCM elderly patients. A PPK model was established to estimate the individual VCM CL for elderly patients, which could be applied for individualising doses in the target population.
基金Supported by the Significant Drug Research and Development in Important State Science and Technology Specific and Key Technique Research(No.2009ZX09502-030)Visiting Fellow Joint Innovation Research Project of the China Academy of Chinese Medicial Sciences(No.ZZ070834)the Specialty Committee of Evaluation of Postmarketing Chinese Medicines of World Federation of Chinese Medicine Societies
文摘Although many population pharmacokinetics（PPK） researches have been conducted on chemical drugs,few have been in the field of Chinese medicine（CM）.Each ingredient in CMs possesses different pharmacokinetic characteristics,therefore,it is important to develop methods of PPK studies on them to identify the differences in CM drug safety and efficacy among the population subgroups and to conduct quantitative studies on the determinants of CM drug concentrations.To develop an expert consensus on study design and implementation for PPK of CM,in August 2013,6 experts in the field of PPK,CMs pharmacology,and statistics discussed problems on the PPK research protocol of CMs,and a consensus was reached.The medicines with toxicity and narrow therapeutic windows and with wide range of target population or with frequent adverse reactions were selected.The compositions with definite therapeutic effects were selected as indices,and specific time points and sample sizes were designed according to standard PPK design methods.Target components were tested through various chromatography methods.Total quantity statistical moment analysis was used to estimate PPK parameters of each component and PPK models reflecting the trend of CMs（which assists in reasonable adjustments on clinical dosage）.This consensus specifies the study design and implementation process of PPK.It provides guidance for the following：post-marketing clinical studies,in vivo investigations related to the metabolism in different populations,and development and clinical adjustment of dosages of CMs.
文摘Objective To study the population pharmacokinetic(PPK)profiles of linezolid in Chinese healthy volunteers and infected patients.Methods Linezolid 600 mg was administered to 31 Chinese healthy volunteers with a single dose and to 57 infected patients every 12 h for at least5 doses.High performance liquid chromatography was applied to determine the plasma concentration of linezol-
基金National Natural Science Foundation of China (Grant No. 30472195)
文摘To investigate pharmacokinetics ofbaicalin after an oral administration of different Shuang-Huang-Lian （SHL） formulations to rats. Different SIlL formulations were orally administered to rats. The concentrations of baicalin in rat plasma were determined by HPLC, the non-compartmental pharmacokinetic parameters and population pharmacokinetic parameters of baicalin were estimated by WinNonlin and NONMEM. The plasma concentration profiles of baicalin demonstrated double-peak phenomenon except for group microemulsion prescription 2. Population pharmacokinetic model developed includes four covariates, which were the effect of formulation （FORM） on CL/F and V/F, the effect of body weight （BW） on Ka, and the effect of gender （GEND） on V/F. Numbers 1 to 6 denote SHL formulation decoction, oral liquid, colloidal solution, microemulsion prescription 1, microemulsion prescription 2 and granule, respectively. The equations for the parameters are as following： CL/F = （0.432 ＋ 0.529）. e^ηCl L/h if formulation was 2 or 6, otherwise CL/F = 0.432. e^ηCl L/h ; V/F = （11.3- 4.03 - 3.87. GEND）. e^ηv L if formulation was 5, otherwise V/F = （11.3 - 3.87. GEND）. e^ηv L ; Ka = 0.475. [1 - 0.0223. （BW - 195.1）]. e^ηKah^-1. SHL formulations have significant effects on the nharmacokinefic narameters.
基金National Natural Science Foundation of China(Grant No. 30472165) the 985 Projects of the State KeyLaboratory of Natural and Biomimetic Drugs (Grant No.268705077280).
文摘Aim To develop a method to estimate population pharmacokinetic parameters with the limited sampling time points provided clinically during therapeutic drug monitoring. Methods Various simulations were attempted using a one-compartment open model with the first order absorption to determine PK parameter estimates with different sampling strategies as a validation of the method. The estimated parameters were further verified by comparing to the observed values. Results The samples collected at the single time point close to the non-informative sampling time point designed by this method led to bias and inaccurate parameter estimations. Furthermore, the relationship between the estimated non-informative sampling time points and the values of the parameter was examined. The non-informative sampling time points have been developed under some typical occasions and the results were plotted to show the tendency. As a result, one non-informative time point was demonstrated to be appropriate for clearance and two for both volume of distribution and constant of absorption in the present study. It was found that the estimates of the non-informative sampling time points developed in the method increase with increases of volume of distribution and the decrease of clearance and constant of absorption. Conclusion A rational sampling strategy during therapeutic drug monitoring can be established using the method present in the study.
文摘Caffeine is a commonly ingested psychoactive substance which affects alertness and cognition. A clinical study was conducted to determine the effect of orally ingested caffeine on visual analogue scale (VAS) responses in healthy, moderate caffeine-consuming volunteers through the use of population pharmacokinetic-pharmacodynamic (PK-PD) modeling. Twelve subjects were recruited for a three-period cross-over study which utilized caffeine containing beverages. Each visit included 8-hour blood plasma and VAS response collection for PK and PD assessment respectively. The VAS used in the study, also called the caffeine analog scale, has been previously validated for caffeine. Population PK-PD modeling was conducted with NONMEM 7.2. Simultaneous and sequential modeling of PK-PD was attempted. Final model selection was based on parameter estimate precision, diagnostic plots, and visual predictive check (VPC) plots. Results showed that a one-compartment open model with first-order absorption and elimination best described the pharmacokinetics of caffeine. Sequential PK-PD modeling was successful and an effect compartment model with linear slope and baseline parameter best described caffeine pharmacodynamics. Diagnostic plots showed no major bias and VPC plots showed agreement between observations and predictions. The model was able to link VAS responses to caffeine concentration in healthy volunteers and may be useful in clinical trial simulations and design.
基金The National Natural Science Foundation of China(No.11171065,81130068)the Natural Science Foundation of Jiangsu Province(No.BK2011058)the Fundamental Research Funds for the Central Universities(No.JKPZ2013015)
文摘The nonlinear mixed-effects model with stochastic differential equations （SDEs） is used to model the population pharmacokinetic （PPK） data that are extended from ordinary differential equations （ODEs） by adding a stochastic term to the state equation. Compared with the ODEs, the SDEs can model correlated residuals which are ubiquitous in actual pharmacokinetic problems. The Bayesian estimation is provided for nonlinear mixed-effects models based on stochastic differential equations. Combining the Gibbs and the Metropolis-Hastings algorithms, the population and individual parameter values are given through the parameter posterior predictive distributions. The analysis and simulation results show that the performance of the Bayesian estimation for mixed-effects SDEs model and analysis of population pharmacokinetic data is reliable. The results suggest that the proposed method is feasible for population pharmacokinetic data.
基金The 115th Project of Legionary Medical Treatment and Public Health(Grant No.06G023)
文摘The aim of this study was to develop a combined population pharmacokinetic （PPK） model for losartan and its active metabolite E-3174 in five Chinese ethnicities for individualized drug therapy in clinical practice. HPLC method was used to determine the blood levels of losartan and E-3174 simultaneously. One-, two- and three-compartment models were fitted to plasma concentration time data of 50 Chinese healthy subjects （including Han, Mongolian, Korean, Hui and Uigur） using nonlinear mixed-effect modeling （NONMEM）. From the basic model of losartan, the effects of demography and biochemical covariates were investigated, which were added one by one by the forward inclusion and backward elimination. The final models of losartan and E-3174 were connected by first order or transit compartment model. Pharmacokinetic parameters of losartan and its active metabolite E-3174 were assessed simultaneously in one integrated model with the plausible covariates on the key pharmacokinetic parameters of E-3174. Nonparametric bootstrap was used for the model stability validation. The data of losartan were best described using a two-compartment model with linear elimination. The time to reach Cmax of losartan and E-3174 were obtained to be 0.9 and 3.8 h, respectively. Two transit compartments were chosen with adequate fit of the delayed Tmax of E-3174. The population estimates for transformation of losartan to E-3174 was about 73.9%. Ethnicity factor showed significant influence on the non-metabolizing E-3174 clearance CL10, the peripheral compartment clearance CL2 and the central compartment volume Vj of losartan and also has a significant effect on the transit rate （Kt）. A total of 925 out of 1000 iterations succeeded in minimization. The PPK models were steady and reliable. Ethnicity factor showed significant influence on both losartan clearance and the transition from losartan to E-3174, no covariate influencing the PK parameters of E-3174 was identified.
基金Janssen Research & DevelopmentChina，Pfizer Scholarship for Pharmacometrics during this project
文摘A tablet consisting of direct-acting antiviral agents,ledipasvir（a NS5 A protein inhibitor） and sofosbuvir（a NS5 B polymerase inhibitor）,is the first fixed-dose preparation used in the antiviral therapy of hepatitis C.A model-based meta-analysis of ledipasvir and GS331007,the primary metabolite of sofosbuvir,enabled the integration of pharmacokinetic（PK） information from separate clinical trials and the quantitative characterization of the population pharmacokinetics of these two drugs.A systematic publication search was conducted for the clinical studies of ledipasvir and sofosbuvir.A total of 401 arm-level aggregate concentrations of GS331007 and 188 concentrations of ledipasvir were used for PK modeling.A two-compartment disposition model was used for both ledipasvir and GS331007.Zero-order absorption was applied for ledipasvir PK modeling,and a combined zero- and first-order absorption was used for the modeling of GS331007.Absorption lag was observed in concentration-time profiles of both ledipasvir and GS331007.To aid the development of direct-acting antiviral drugs,our established PK models provided a basis for the further PK-viral kinetic studies of ledipasvir and sofosbuvir.
