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Caspofungin is the firs t echinocandin antifungal drug approved for serious fungal infections caused by Candida or Aspergillus. Currently ，caspofungin has been recommended as the first-line treatment for invasive Candida and the second-line treatment for invasive Aspergillus，for its safety and tolerability. However ，there are still probability of pharmacokinetic variability and the risk of low exposure in different populations. Herein the population pharmacokinetics-pharmacodynamics studies of caspofungin in children and adults were reviewed. The results indicate that the body surface area was the main factor affecting the distribution and clearance of caspofungin in pediatric patients. In adults ，the two-compartment model fits the caspofungin behavior best in vivo with the primary covariates of body weight and albumin level. The efficacy of caspofungin might be related to pharmacokinetics-pharmacodynamics parameters ，such as the ratio of area under blood concentration time curve to minimum inhibitory concentration （AUC/MIC），the ratio of peak concentration to minimum effective concentration （cmax/MEC）.
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Objective::To study the pharmacokinetics of sinapic acid from stir-fried Raphani Semen in normal rats and the correlation between pharmacokinetics-pharmacodynamics (PK-PD) in asthma rats. Method::Normal rats received 4.5, 9, 18 g·kg-1 of stir-fried Raphani Semen by oral administration, respectively. Blood was taken from ophthalmic venous plexus at different time points according to the experimental design, the plasma concentration of sinapic acid was analyzed by UHPLC-MS/MS, and data analysis was performed using DAS 3.2.8 software to obtain the pharmacokinetic parameters. Rat asthma model was established by intraperitoneal injection of ovalbumin with aluminum hydroxide, and treated with ethanol extract of stir-fried Raphani Semen (low and high doses of 4.5, 9 g·kg-1). After treatment for 3 weeks, taking blood at different time points, plasma and serum were separated. UHPLC-MS/MS was established for the determination of plasma concentration of sinapic acid, contents of interleukin-5 (IL-5), immunoglobuin E (IgE), tumor necrosis factor-α (TNF-α) in serum at different time points were detected by enzyme-linked immunosorbent assay (ELISA), DAS 3.2.8 software was used for PK-PD model fitting and data analysis. Result::After normal rats were administrated with low, medium and high doses of stir-fried Raphani Semen, the peak concentration (Cmax) of sinapic acid in plasma were (29.35±10.32), (62.70±27.47), (137.33±40.95) μg·L-1, its area under the curve (AUC0-t) were (92.83±27.16), (240.74±75.09), (633.95±195.88) μg·L-1·h, its peak time (Tmax) were (2.58±0.80), (3.00±0), (5.50±1.23) h, respectively. Compared with the low dose group, AUC0-t and mean retention time (MRT0-t) were all increased in the medium and high dose groups, showing statistical differences (P<0.05, P<0.01). The linear relationship of AUC0-t in sinapic acid was good within the dose range of 4.5-18 g·kg-1. After treating with ethanol extract of stir-fried Raphani Semen for 0.083, 0.167 h, compared with the model group of asthmatic rats, serum levels of IL-5, IgE, TNF-α of the medication groups were decreased to different degrees (P<0.05, P<0.01). Cmax of sinapic acid in the low and high dose groups were (58.43±29.94), (61.16±18.79) μg·L-1, its AUC0-t were (188.75±37.07), (247.90±36.89) μg·L-1·h, respectively. AUC0-t, apparent volume of distribution (Vz/F) and clearance rate (CLz/F) all increased significantly with the increase of dose. The best pharmacokinetic model of sinapic acid was fitted as a one-compartment model for extravascular administration, PK-PD model may be applicable to indirect connection model. Conclusion::The plasma concentration of sinapic acid is correlated with contents of IL-5, IgE and TNF-α, dosage and functional state (pathological or physiological state) can affect the pharmacokinetic behavior of sinapic acid from stir-fried Raphani Semen in rats, and it has a certain correlation with the anti-asthmatic effect.
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The research and development of monoclonal antibodies (mAbs) is a rapidly developing field. From the first generation of murine mAbs to the fourth generation of fully human mAbs, the efficacy and safety of mAbs in the treatment of various diseases have been continuously improved. In order to regulate the development and evaluation of mAbs, drug regulatory agencies and pharmacopeias of America and China have tried to issue feasible test procedures and acceptance criteria for quality evaluation of mAbs and biosimilars. Mass spectrometry (MS) technique with high sensitivity, resolution, selectivity, and specificity has become an important tool to evaluate the quality characteristics of monoclonal antibody-related products or specify mAb quality. The research of MS-based monoclonal antibody study involves structure characterization, impurity analysis, pharmacokinetics/pharmacodynamics (PK/PD), etc. This review focuses on the current quality control requirements of mAb related products and the development of MS technique for mAb quality characterization and specification. It is expected to provide information and references for evaluating the quality of monoclonal antibodies under research and development.
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Model-informed drug development (MIDD) refers to the application of various mathematical models in drug development, in order to facilitate the decision-making process. There have been common and mature applications of MIDD to address drug development and regulatory questions in interactional industries and advanced regulatory agencies, especially the US FDA. However, its application in innovative drug development is relatively rare in China. Representative case studies, clinical pharmacology review ex-periences, and relevant guidelines are reviewed in this article to present a preliminary discussion on the main applications of MIDD. Additionally, several suggestions for the application of MIDD in new drug development as well as general considerations for new drug registration are proposed in this paper, for the discussion or reference of industries and researchers.
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Objective::A multi-organ chip of intestine-liver-breast cancer was constructed based on microfluidic technology and used for pharmacokinetics-pharmacodynamics (PK-PD) study of drugs in vitro. Method::A multi-organ chip comprising a 4-layer polydimethylsiloxane (PDMS) substrate and a 2-layer poly(methyl methacrylate) (PMMA) cover was constructed by microfluidic technology. The connection between cells was investigated by staining the 21-day-grown human colon cancer cell line Caco-2 cell layer and the 3-day-grown human umbilical vein endothelial cell line HUVEC cell layer with CellTracker Red/Green and Hoechst, respectively. The transmission rates of 2 g·L-1 fluorescein sodium and 33.28 mg·L-1 propranolol acrossing the cell layer were employed to verify the function of the constructed intestinal module. The metabolic level of the liver module was investigated by comparing the inhibition rate of 125 μmol·L-1 cyclophosphamide against human breast cancer cell line MCF-7 cells treated with human hepatoma cell line HepG2 cells in a conventional well plate and chip liver module for 48 h. The secretion of albumin by HepG2 cells in the chip was detected to verify the synthesis function of hepatic module. Caco-2 cell layer, HUVEC cell layer, HepG2 cell layer, MCF-7 cell layer and dialysis membrane were assembled on the chip, the culture medium containing 55 mg·L-1 propranolol was injected into the upper channel of the chip for 4 h, and then changed into the normal culture solution. The mass concentration of propranolol in the lower circulating culture medium at each time point within 72 h was determined, and the drug-time curve was drawn. The culture medium containing 125 μmol·L-1 cyclophosphamide, 5 μmol·L-1 paclitaxel, 50 μmol·L-1 capecitabine was injected into the circulating fluid in the upper layer of the chip, in order to study the inhibition rates of the three anti-tumor drugs on the MCF-7 cell layer on the chip within 72 h, and the results were compared with those of the 96-well plate. Result::The constructed chip performed well. The Caco-2 and HUVEC cell layers were tightly connected. The transmission of fluorescein sodium and propranolol between the cell layers demonstrated that the constructed intestinal module had good absorption and transport function. The inhibition rate of MCF-7 by 125 μmol·L-1 cyclophosphamide after metabolism of HepG2 cells on the well plate was 22.12%, and the inhibition rate of MCF-7 by the unmetabolized cyclophosphamide was 1.84%. The inhibition rate of MCF-7 increased to 32.13%after injected 125 μmol·L-1 cyclophosphamide from the upper layer of the chip liver module, and the inhibition rate of MCF-7 after injection from the lower layer of the chip liver module was 7.23%. The mass concentration of propranolol on the chip changed with time, which was basically consistent with that in vivo. The inhibition rate of MCF-7 on the plate with 125 μmol·L-1 cyclophosphamide was lower than that on the chip, and the inhibition rates of MCF-7 on the plate with 5 μmol·L-1 paclitaxel and 50 μmol·L-1 capecitabine were higher than those on the chip. Conclusion::The constructed multi-organ chip of intestine-liver-breast cancer has the absorption and transport function of the intestine and the metabolic function of the liver. The chip can reflect the pharmacokinetic properties of propranolol in vivo, and can be used for pharmacodynamic studies of paclitaxel and capecitabine.
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Objective:To study on the correlation between integrated pharmacokinetics and pharmacodynamic effects of five active components(oxidized paeoniflorin,paeoniflorin,quercetin,gallic acid, paeonol) in Moutan Cortex. Method:Rats were divided into blank group,model group(syndrome of blood-heat and blood stasis) and drug-administered group.The concentration of five active components in serum were detected with UPLC-MS at different time points after being administrated ethanol extract of Moutan Cortex.The integrated concentrations were calculated according to area under the curve(AUC) self-defined weighting coefficiency.At the same time,the enzyme-linked immunosorbent assay(ELISA) was used to determine the contents of thromboxane B2(TXB2) and 6-keto-prostaglandin F1α(6-keto-PGF1α) in serum at different time points,and then correlation between pharmacodynamics and integrated pharmacokinetics of these five active ingredients was analyzed. Result:At different time points(0.083,0.25,0.5,0.75,1,2,3,4,6,8,10,12 h),the integrated plasma concentrations of these five active ingredients in Moutan Cortex(158.65,174.60,220.13,227.23,244.31,251.51,404.28,654.39,472.62,355.04, 231.56,199.40 mg·L-1) had a good correlation with concentration of TXB2(264.44,261.03,284.93,273.30,264.04, 278.90,274.83,303.58,260.03,264.78,264.40,256.62 μg·L-1) and value of TXB2/6-keto-PGFlα(4.50,4.47,3.66,3.37, 3.29,3.66,3.71,4.30,3.63,3.65,3.75,3.66). Conclusion:There is a good correlation between the dynamic changes in vivo of active components from Moutan Cortex and pharmacodynamic effects of activating blood circulation of this herb.
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Precision medicine has become a new mode of modern medicine, and personalized medication is the important embodiment of clinical application of precision medicine. The advances of life science technologies greatly facilitated precision medicine, and also promoted the shift of the mode of clinical pharmacy care from rational drug use and individualized medication to precision medication. To achieve"one person, one mode" clinical dosage regimens,it is necessary to rely on the supports of advanced life science technologies and precisely analyzing and accurately characterizing the biomarker clusters related to individual differences among patients, pathological differences of disease, and disease progression. This article illustrated the recent advances in the application of pharmacokinetics/pharmacodynamics, omics technology and liquid biopsy to the design of dosage regimen, prediction of therapeutic effect and adverse drug reactions, etc. in the era of precision medicine. Furthermore, the development direction of the new model of clinical pharmaceutical care faced on the precision medicine is prospected.
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Study on the integrated pharmacokinetics/pharmacodynamics (PK/PD) model of rhubarb in rats with yang-deficiency constipation based on the principle of traditional Chinese medicine system. The rat model of yang-deficiency constipation was established using vinegar and ice water containing activated carbon. The blood samples with 0.5 mL were collected from orbital venous plexus at 0, 5, 10, 15, 30, 60, 120, 240, 480, 720, 1 440 min time points after oral administration of rhubarb decoction, and the dosage is equivalent to crude drug 2.5 g·kg-1. The concentration of aloe-emodin, rhein, emodin and chrysophanol in rat plasma were determined by HPLC, and ELISA method was used to detect the activities of motilin (MTL), gastrin (GT), endothelin (ET) and vasoactive intestinal peptide (VIP) at different time points in serum. SPSS 21.0 software was used for analysis of component correlation and principal component, and WinNonlin 6.30 software was used to fit PK/PD model. Compared with the pharmacokinetic parameters of normal rats, in addition to emodin in the model rats showed characteristics of good absorption and slow to elimination; the content of MTL in model rats was significantly lower than that in normal rats. The composite values of the concentration and effect obtained by principal component analysis were connected by Sigmoid-Emax model. We established the integrated PK/PD model of rhubarb in treating yang-deficiency constipation to provide a new research direction for the material basis and mechanism of rhubarb treatment of yang deficiency constipation.
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OBJECTIVE: To evaluate and optimize the treatment regimen of cephalosporins based on Monte Carlo simulation and the pharmacokinetics /pharmacodynamics (PK/PD) model. METHODS: The treatment regimens of cefradine, cefuroxime, ceftriaxone and cefepime are 0.75 g qid, 1 g qid, 2 g bid and 2 g tid. And a total of 903 strains from eight species were collected. The minimum inhibitory concentration (MIC) was measured by trace broth dilution method. Monte Carlo simulation was used to simulate the regimens against Escherichia coli, Bacillus, Klebsiella pneumoniae, Acinetobacter baumannii, Citrobacter, Staphylococcus aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa. Then, the cumulative fraction of response (CFR) was calculated. RESULTS: Cefhradine and cefuroximes' rates of resistance were higher (47.31% - 100%), the cumulative reaction scores(CFR) were all less than 90%. Cefuroxime has desirable regimen for Escherichia coli, Klebsiella pneumoniae, Citrobacter and Streptococcus pneumoniae. Cefepime has at least one dose regimen's CFR for more than 90%, and cephalosporins is consistent with time-dependent drug characteristics. CONCLUSION: For the treatment of infectious diseases, the choice of cephalosporins should be used to follow the principles of antibiotics. Target therapy should be used to test the pathogen susceptibility test, according to the value of MIC to simulate the corresponding dosing regimen, to achieve individualized administration.
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Objective To evaluate whether individualized dosage regimen based on therapeutic drug monitoring (TDM) is beneficial for improving the rate of pharmacokinetics/pharmacodynamics (PK/PD) reaching the standard and anti-infection efficacy. Methods Totally, 36 cases in the intensive care unit ( ICU ) of Nanjing Drum Tower Hospital using meropenem during January 2015 to December 2015 were collected, and divided into intervention group and control group. Results On the fourth day of administration, meropenem concentration in intervention group was significantly higher than that of the control group (22.5 μgmL-1 and 17.5 μgmL-1, respectively, P=0.007).With minimal inhibitory concentration (Cmin)>8 μgmL-1 serving as target, the rate of reaching the standard was both 22. 2% on day 2, 100. 0% and 72. 2% on day 4 in intervention group and control group, respectively (P=0.015). With minimal inhibitory concentration (Cmin) >32 μgmL-1 serving as target, the rate of reaching the standard was both 0 on day 2, 38. 9% and 5. 5% on day 4 in intervention group and control group, respectively (P=0.015). The clinical curative rate of the intervention group and control group was 83.3% and 72.2%, respectively (P=0.437), and the failure rate was 16.7% and 27.8%, respectively.Bacteria clearance rate was 88.9%and 55.5% in the intervention group and control group, respectively(P<0.05). Conclusion Individualized dosage regimen based on TDM in ICU patients is beneficial to improving the rate of PK/PD reaching the standard and anti-infection efficacy.
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Objective To evaluate whether individualized dosage regimen based on therapeutic drug monitoring (TDM) is beneficial for improving the rate of pharmacokinetics/pharmacodynamics (PK/PD) reaching the standard and anti-infection efficacy. Methods Totally, 36 cases in the intensive care unit ( ICU ) of Nanjing Drum Tower Hospital using meropenem during January 2015 to December 2015 were collected, and divided into intervention group and control group. Results On the fourth day of administration, meropenem concentration in intervention group was significantly higher than that of the control group (22.5 μgmL-1 and 17.5 μgmL-1, respectively, P=0.007).With minimal inhibitory concentration (Cmin)>8 μgmL-1 serving as target, the rate of reaching the standard was both 22. 2% on day 2, 100. 0% and 72. 2% on day 4 in intervention group and control group, respectively (P=0.015). With minimal inhibitory concentration (Cmin) >32 μgmL-1 serving as target, the rate of reaching the standard was both 0 on day 2, 38. 9% and 5. 5% on day 4 in intervention group and control group, respectively (P=0.015). The clinical curative rate of the intervention group and control group was 83.3% and 72.2%, respectively (P=0.437), and the failure rate was 16.7% and 27.8%, respectively.Bacteria clearance rate was 88.9%and 55.5% in the intervention group and control group, respectively(P<0.05). Conclusion Individualized dosage regimen based on TDM in ICU patients is beneficial to improving the rate of PK/PD reaching the standard and anti-infection efficacy.
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Objective To investigate the entry points for clinical work of intensive care unit (ICU) pharmacists.Methods Through combination with daily work and referring the domestic and foreign literature,the characteristics of ICU medications were discussed to find out the entry point for clinical work of ICU pharmacists.Results ICU patients particularly need individualized pharmaceutical care because of the special pathophysiological characteristics and medicine use.Conclusion ICU pharmacists should provide pharmaceutical care based on Pharmacokinetics/pharmacodynamics knowledge and focus on the drug dosage adjustment,drug interactions and adverse event prevention.
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Objective To understand the changing characteristics of drug concentration in the serum and cerebrospinal fluid(CSF) after intravenous (IV) drip of norvancomycin in patients after neurosurgery procedure.Methods Patients with surgical cavity/ventricular drainages after neurosurgery procedure in a hospital in 2014 were selected, and they were divided into 2 groups according to the administration modes (12 in each group), conventional administration group: 0.8 g norvancomycin IV drip for 60 minutes, repeated every 12 hours;continuous administration group, 0.8 g norvancomycin, IV drip for 60 minutes, followed by 0.4 g of IV drip for 11 hours, then 0.4 g for 12 hours, serum and CSF specimens were collected at different time points after administration, concentration of norvancomycin was determined.Results Serum norvancomycin concentration reached a peak of (55.52±26.04) and (59.22±41.88) mg/L in conventional administration group and continuous administration group respectively, 24-hour serum concentration were (8.21±6.04) and (9.11±5.09)mg/L respectively;CSF norvancomycin concentration reached a peak of (16.31±11.15) and (8.82±8.91)mg/L in conventional administration group and continuous administration group respectively, 24-hour CSF concentration were (6.12±2.34)and (5.71±4.72)mg/L respectively;CSF penetration rate of conventional administration group was calculated by ratio of area under curve (AUCCSF/AUCserum), at 0-12 and 12-24 h hour were 63.3% and 59.0% respectively;in continuous administration group were 25.4% and 47.4% respectively.According to 95% of the minimum inhibitory concentration (MIC90) 2 mg/L of target bacteria methicillin-resistant Staphylococcus aureus (MRSA), AUC0-24/MIC90 in conventional administration group and continuous administration group were 192 and 184 respectively.Conclusion For patients who receives early use of standard dose of norvancomycin after neurosurgery procedure, CSF drug concentration after convention and continuous administration of norvancomycin can both reach MIC90 against target bacteria.
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OBJECTIVE:To provide reference for clinical individual medication of voriconatole. METHODS:The distribution of MIC of voriconazole to Aspergillus fumigatus and Candida albicans were summarized as well as the pharmacokinetic parameters of voriconazole in different populations. Using probability of target attainment(PTA)and cumulative fraction of response(CFR)as indexes,crystal ball software 11.1.2.4 was used for Monte Carlo simulation of different dosage regimens of same population and same dosage regimen of different populations. RESULTS:For children with impaired immunity,when the drug doses of were 4,6 mg/kg and MIC was lower than 0.125 mg/L,PTA was higher than 90%;when the drug doses was increased to 8 mg/kg and MIC was lower than 0.125 mg/L,PTA was higher than 90%. For different populations receiving same dosage regimens(4 mg/kg),MIC of teenagers with impaired immunity was lower than 0.25 mg/L and those of healthy adults,patients underwent hematopoietic stem cell transplantation and adults with impaired immunity were all lower than 0.5 mg/L,PTA was higher than 90%. CFR to A. fumigatus were 42.53%,58.41%,77.74%,70.16%,89.40%,93.72%,95.42% and CFR to C. albicans were 96.68%,97.13%,97.94%, 97.54%,98.07%,98.28%,98.35%among children with impaired immunity receiving different drug doses(4,6,8 mg/kg)and dif-ferent populations receiving drug dose of 4 mg/kg(teenagers with impaired immunity,healthy adults,patients underwent hemato-poietic stem cell transplantation,adults with impaired immunity). CONCLUSIONS:Various dosage regimens of different popula-tions included in this study could effectively control C. albicans infection. It is necessary to increase the drug dose of children and teenagers with impaired immunity in order to meet the needs of A. fumigatus infection treatment.
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This study was aimed to establish the pharmacokinetics-pharmacodynamics (PK-PD) model of ginsenoside Rb1 following the intravenous administration of Shengmai injection in subjects with stable angina pectoris.A total of stable angina pectoris were selected and received Shengmai injection for 14 days.Plasma samples were collected at different time points.Plasma concentrations of ginsenoside Rb1 were determined by liquid chromatography-mass spectrometry (LC/MS).The concentration-time curves (AUC) were drawn,and then the PK parameters were calculated.The systolic pressure and diastolic pressure were monitored,and the combined PK-PD model was established based on the theory of effect compartment.The results showed that PK of ginsenoside Rb1 conformed to a mono-compartment model.The effect of Shengmai injection lagged behind the concentrations of ginsenoside Rb1 in plasma.The effect exhibited good correlation with ginsenoside Rb1 in effect compartment.The relationship between effect and plasma concentrations fits the Inhibitory Effect Imax model.It was concluded that the study successfully established the combined PK-PD model of ginsenoside Rb1 in subjects with angina pectoris.The model can efficiently evaluate the effective substance of Shengmai injection.
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Objective To evaluate the reliability of using imipenem,meropenem,cefoperazonesulbactam,piperacillin-tazobactam in the treatment of hospital-acquired Gram-negative bacterial infections with Monte Carlo simulation(MCS).Methods The MIC of the four agents collected from hospital-acquired infections were detected in accordance with broth dilution method of Clinical and Laboratory Standard Institute (CLSI).MCS were conducted with MICs and the pharmacokinetics parameters of the four agents based on conventional dose regimens.The cumulative fraction of response (CFR) of time over MIC target attainment in different dosing regimen were generated.Results A total of 2 541 strains,including 2 093 strains of Enterobacteriaceae and 448 strains of glucose non-fermentative bacilli were collected.The MIC90 of imipenem and meropenem against Enterobacteriaceae were less than 1 mg/L in general,whereas MICg0 of two agents with β-1actamase inhibitors was around 64 mg/L.As to glucose non-fermenting bacteria,MICs of all the four agents were very high,especially to Acinetobacter baumannii,which indicated MIC50 more than 32 mg/L.MCS revealed that carbapenems had significantly higher CFR than those with β-1actamase inhibitors.Imipenem and meropenem (1 g,q8 h) obtained CFRs of 74.69％ and 81.42％,respectively.The CFR of cefoperazone-sulbactam (2 g,q8 h) and piperacillin-tazobactam (4 g,q6 h) (both excluding β-1actamase inhibitors) were just 49.59％ and 27.66％ respectively,which increased after excluding A.baumannii in piperacillin-tazobactam.Conclusions The conventional dose regimens of imipenem and meropenem are reliable for the empiric therapy of Gram-negative hospital-acquired bacterial infections.Piperacillin-tazobactam is suggested to use with higher doses or prolonged infusion time to satisfy the time of drug concentration exceeded the MIC (T ＞ MIC) requirement.More clinical studies of cefoperazone-sulbactam should be conducted to optimize its regimen and guarantee its efficacy.
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Durante a cirurgia de revascularização do miocárdio com circulação extracorpórea e hipotermia (CEC-H) ocorre alteração na efetividade do propofol e na sua farmacocinética realizada a partir das concentrações plasmáticas do propofol total no decurso do tempo. A ligação do propofol à proteína plasmática parece estar alterada em consequência de diversos fatores incluindo a hemodiluição e a heparinização que ocorre no início da circulação extracorpórea, uma vez que se reportou anteriormente que a concentração plasmática do propofol livre aumentou durante a realização da circulação extracorpórea normotérmica. Por outro lado, a infusão alvo controlada é recomendada para manter a concentração plasmática do propofol equivalente ao alvo de 2 µg/mL durante a intervenção cirúrgica com CEC-H. Se alterações significativas na hipnose do propofol ocorrem nesses pacientes, então o efeito aumentado desse agente hipnótico poderia estar relacionado à redução na extensão da ligação do fármaco as proteínas plasmáticas; entretanto, o assunto ainda permanece em discussão e necessita de investigações adicionais. Assim, o objetivo do estudo foi investigar as concentrações plasmáticas de propofol livre em pacientes durante a revascularização do miocárdio com e sem o procedimento de CEC-H através da abordagem PK-PD. Dezenove pacientes foram alocados e estratificados para realização de cirurgia de revascularização do miocárdio com circulação extracorpórea (CEC-H, n=10) ou sem circulação extracorpórea (NCEC, n=9). Os pacientes foram anestesiados com sufentanil e propofol alvo de 2 µg/mL. Realizou-se coleta seriada de sangue para estudo farmacocinético e o efeito foi monitorado através do índice bispectral (BIS) para medida da profundidade da hipnose no período desde a indução da anestesia até 12 horas após o término da infusão de propofol, em intervalos de tempo pré-determinados no protocolo de estudo. As concentrações plasmáticas foram determinadas através de método bioanalítico pela técnica de cromatografia líquida de alta eficiência. A farmacocinética foi investigada a partir da aplicação do modelo aberto de dois compartimentos, PK Solutions v. 2. A análise PK-PD foi realizada no Graph Pad Prisma v.5.0 após a escolha do modelo do efeito máximo (EMAX sigmóide, slope variável). Os dados foram analisados utilizando o Prisma v. 5.0, p<0,05, significância estatística. As concentrações plasmáticas de propofol total foram comparáveis nos dois grupos (CEC-H e NCEC); entretanto o grupo CEC-H evidenciou aumento na concentração do propofol livre de 2 a 5 vezes em função da redução na ligação do fármaco às proteínas plasmáticas. A farmacocinética do propofol livre mostrou diferença significativa entre os grupos no processo de distribuição pelo prolongamento da meia vida e aumento do volume aparente, e no processo de eliminação em função do aumento na depuração plasmática e redução na meia vida biológica no grupo CEC-H. A escolha do modelo EMAX sigmóide, slope variável foi adequada uma vez que se evidenciou alta correlação entre os valores do índice bispectral e as concentrações plasmáticas do propofol livre (r2>0.90, P<0.001) para os pacientes investigados
During coronary artery bypass grafting (CABG) surgery with cardiopulmonary bypass (CPB) profound changes occur on propofol effect and on kinetic disposition related to total drug plasma measurements in these patients. It was reported that drug plasma binding could be altered as a consequence of hemodilution and heparinization before starts CPB since free propofol plasma levels was increased by twice under normothermic procedure. In addition, the target controlled infusion (TCI) is recommended to maintain propofol plasma concentration (2 µg/mL) during CABG CPB-H intervention. However, whether significant changes that occur in propofol hypnosis in these patients could be related to the reduction on the extension of drug plasma binding remain unclear and under discussion until now. Then, the objective of this study was to investigate propofol free plasma levels in patients undergoing CABG with and without CPB by a pharmacokinetics-pharmacodynamics (PK-PD) approach. Nineteen patients were scheduled for on-pump coronary artery bypass grafting (CABG-CPB, n=10) or off-pump coronary artery bypass grafting (OPCABG, n=9) were anesthetized with sufentanil and propofol TCI (2 µg/mL). Blood samples were collected for drug plasma measurements and BIS were applied to access the depth of hypnosis from the induction of anesthesia up to 12 hours after the end of propofol infusion, at predetermined intervals. Plasma drug concentrations were measured using high-performance liquid chromatography, followed by a propofol pharmacokinetic analysis based on two compartment open model, PK Solutions v.2; PK-PD analysis was performed by applying EMAX model, sigmoid shape-variable slope and data were analyzed using Prisma v. 5.0, considering p<0.05 as significant difference between groups. The total propofol plasma concentrations were comparable in both groups during CABG; however it was shown in CPB-group significant increases in propofol free plasma concentration by twice to fivefold occur as a consequence of drug plasma protein binding reduced in these patients. Pharmacokinetics of free propofol in CPB-H group compared to OPCAB group based on two compartment open model was significantly different by the prolongation of distribution half-life, increases on plasma clearance, and biological half-life shortened. In addition, the kinetic disposition of propofol changes in a different manner considering free drug levels in the CPB-H group against OPCAB group as follows: prolongation of distribution half-life and increases on volume of distribution, remaining unchanged biological half-life in spite of plasma clearance increased. BIS values showed a strong correlation with free drug levels (r2>0.90, P<0.001) in CPB-H group and also in OPCAB group by the chosen EMAX model sigmoid shape-variable slope analyzed by GraphPad Prisma v.5.0
Subject(s)
Humans , Male , Female , Myocardial Revascularization/methods , Myocardium , Propofol/analysis , Chromatography, High Pressure Liquid/instrumentation , Coronary Artery Bypass, Off-Pump/statistics & numerical data , Extracorporeal Circulation/statistics & numerical data , Hemodilution , Hypotension, Controlled/standards , Hypothermia , Pharmacokinetics , Pharmacologic Actions , PlasmaABSTRACT
Objective: To investigate the in vivo pharmacokinetic progress of hydroxysafflor yellow A (HSYA) from Guhong Injection in cerebal ischemia reperfusion (I/R) injury of rats and the correlation with its anti-oxidation effect. Methods: The equilibrium dialysis method was carried out to determine the plasma protein binding rates of HYSA and HSYA in Guhong Injection. Middle cerebral artery occlusion (MCAO) model rats were iv injected HYSA (4 mg/kg) or Guhong Injection (10 mL/kg). The HPLC method was adopted to determine the plasma concentration of HYSA at different time points to draw the drug-time curve. Meanwhile, glutathione peroxidase (GSH-Px) and lactate dehydrogenase (LDH) activities were determined to draw the time-effect curve. Furthermore, the relationship between pharmacokinetics and pharmacodynamics was analyzed. Results: At the concentration of 2.5, 10, and 25 mg/L, the p plasma rotein binding rates of HYSA were 77.96%, 73.54%, and 76.13%, whereas the plasma protein binding rates of HYSA from Guhong Injection were 68.21%, 58.22%, and 63.17%, respectively. A good linear relationship of HYSA was obtained in the range of 0.01-50 mg/L, the mean recoveries were (99.94 ± 2.82)%, (104.16 ± 1.41)%, and (99.74 ± 1.06)% for low, middle, and high concentration of the samples, respectively. Compared with HYSA group, Guhong Injection significantly increased the AUC of HYSA and decreased the MRT and Vz of HYSA. Furthermore, Guhong Injection increased the content of GSH-Px and decreased the content of LDH. The plasma concentration of HYSA is positively related to the GSH-Px activity and negatively related to the LDH activity. Conclusion: The results indicate that HYSA has the moderate plasma protein binding rate. Compared with HYSA group, the plasma protein binding rate in Guhong Injection group is reduced. Guhong Injection could increase the bioavailability of HYSA to enhance therapeutic efficacy and increase the distribution of HYSA in ischemia rats. Guhong Injection has better anti-oxidant effect, as well as more significant protective effect against cerebral I/R injury than HYSA.
ABSTRACT
The pharmacokinetics/pharmacodynamics ( PK/PD) of antimicrobials aims to establish and evaluate dose-concentration-response relationship, and subsequently to describe and predict the effect-time courses resulting from a drug dose.Nowadays, PK/PD is playing an important role in dosage regimen optimizing, reducing toxicity and drug tolerance of antibiotics.And it is also of great significance in determining susceptibility breakpoints and development in new drug.This paper reviews the progress on PK/PD studies of antibacterial and antifungal agents to provide theoretical basis for safe and effective individual dosage regimens.
ABSTRACT
Many new antiepileptic drugs (AEDs) have been developed in the last two decades, contributing to the optimal treatment for childhood epilepsy. The goal of the treatment is to achieve seizure-free without any side effects, that deteriorates the quality of life by causing negative consequences. The new AEDs have not shown better efficacy, but generally seem to be better tolerated, having fewer systemic reactions and better pharmacokinetics than the established AEDs. The new AEDs have a broad spectrum of activities, which offer new opportunities to patients who have not shown any favorable responses to the established ones. There are more choices when trying to select AEDs for epileptic seizures and syndromes. Majority of the new AEDs have more than one action mechanism. AEDs acting selectively through the GABAergic system are tiagabine and vigabatrin; acting by inhibition of voltagedependent Na+ and Ca2+ channels are lamotirigine, oxcabarbazepine and topiramate; and acting by inhibition of glutamate-mediated excitation are felbamate, topiramate. The pharmacokinetic parameters of the new AEDs compared to the established AEDs, new AEDs have improved in terms of longer half-lives, permitting less frequent daily dosing, reduced potential for drug interactions. Considerations in selecting an AEDs are not only dependent on seizure types or syndromes, side effect profile, action mechanism, drug interaction, pharmacokinetic profile, facility of drug initiation, but also on age and sex of patients. Patients with worsened seizurefrequency or development of new types of seizure after the introduction of AEDs, should be questioned on the previously diagnosed seizure types or syndromes.