scholarly journals POPULATION PHARMACOKINETICS OF 2-OXO-CLOPIDOGREL IN PATIENTS WITH ACUTE CORONARY SYNDROME

2019 ◽  
pp. 058
Author(s):  
Valentina Nikolić ◽  
Slobodan M. Janković ◽  
Dragana Stokanović ◽  
Sandra S. Konstantinović ◽  
Jelena B. Zvezdanović ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Plasma Concentrations ◽  
Total Body Weight ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Aspartate Transaminase ◽  
Mixed Effect ◽  
Bootstrap Analysis ◽  
Coronary Syndrome ◽  
Number Of Patients

The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of 2-oxo-clopidogrel in patients with acute coronary syndrome (ACS). Population pharmacokinetic analysis was performed by using 72 plasma concentrations from the same number of patients (mean age of 60.82±10.76 years; total body weight (TBW) of 73.63±9.67 kg) with ACS using non-linear mixed-effect modeling (NONMEM). Validation of the final PPK model was carried out through the bootstrap analysis with 200 runs and it was used to estimate the predictive performance of the pharmacokinetic model. The typical mean value for 2-oxo-clopidogrel clearance (CL), estimated by the base model (without covariates), in our population was 39.2 l h−1.The value of aspartate transaminase and co-medication with digoxin were determinants of a derived population model. The final regression model for the clearance of 2-oxo-clopidogrel was the following: CL (lh-1) = 1.7 + 1.31*AST + 115*DIGOXIN. The derived PK model describes the clearance of 2-oxo-clopidogrel in patients with ACS, showing that the value of aspartate transaminase and co-medication with digoxin are the most important covariate. This finding will provide the basis for future PK studies.

Population Pharmacokinetic Analysis of Bisoprolol in Patients With Acute Coronary Syndrome

2019 ◽  
Vol 73 (3) ◽  
pp. 136-142 ◽  
Author(s):  
Stefan Momčilović ◽  
Jasmina R. Milovanović ◽  
Slobodan M. Janković ◽  
Andriana Jovanović ◽  
Suzana Tasić-Otašević ◽  
...  
Keyword(s):  
Acute Coronary Syndrome ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Coronary Syndrome

scholarly journals Influence of the OATP Polymorphism on the Population Pharmacokinetics of Methotrexate in Chinese Patients

2019 ◽  
Vol 20 (7) ◽  
pp. 592-600 ◽  
Author(s):  
Zhiqi Wang ◽  
Nan Zhang ◽  
Chaoyang Chen ◽  
Shuqing Chen ◽  
Junyu Xu ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Genetic Factors ◽  
Plasma Concentrations ◽  
Chinese Patients ◽  
Estimation Methods ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Mixed Effect ◽  
The Impact

Background: The Pharmacokinetics of Methotrexate (MTX) has been reported to show significant intersubject variability. MTX is metabolized by SHMT1 and transported by OATP1B1 and OATP1B3 both of which show genetic polymorphisms. The non-genetic and genetic factors may influence the pharmacokinetics of MTX. Objective: This study aimed to determine the pharmacokinetic parameters of MTX in Chinese patients and to investigate the effect of various non-genetic factors and genetic variants of OATP1B1, OATP1B3 on MTX’s pharmacokinetics. Method: MTX concentration and clinical characteristics data were collected from 71 rheumatoid arthritis patients. For each patient, SLC19A1, SHMT1, OATP1B1, and OATP1B3 genotyping were tested. Population pharmacokinetic analysis was performed by Nonlinear Mixed-Effect Modeling (NONMEM). MTX pharmacokinetic properties analysis was executed using the one-compartment pharmacokinetic model which incorporated first-order conditional estimation methods with interaction. Besides, the impact of genetic factors and demographic factors on MTX disposition were explored. Results: All the genotypes of steady-state plasma concentrations and OATP1B1 rs4149056, OATP1B1 rs2306283, and OATP1B3 rs7311358 were determined. The detected blood drug concentration reached the standard. Genotypes were all measured. At the same time, the population pharmacokinetic model of methotrexate was obtained CL(L·h-1) =8.25× e0.167× SNP (SNP: SLCO1B1 388A/A=3; SLCO1B1 388A/G=2; SLCO1B1 388G/G=1); V(L)= 32.8; Ka(h- 1)=1.69. Conclusion: : In our study, it was showed that OATP1B1-388 G>A SNP had a significant effect on CL/F. The factor should be considered when determining MTX dosing. However, prospective studies with a large number of participants are needed to validate the results of this study.

scholarly journals Population Pharmacokinetics and Pharmacogenetics Analysis of Rilpivirine in HIV-1-Infected Individuals

2016 ◽  
Vol 61 (1) ◽  
Author(s):  
Manel Aouri ◽  
Catalina Barcelo ◽  
Monia Guidi ◽  
Margalida Rotger ◽  
Matthias Cavassini ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Plasma Concentrations ◽  
Antiretroviral Drugs ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
Standard Dosage ◽  
Number Of Patients ◽  
Hiv 1

ABSTRACT Rilpivirine (RPV), the latest nonnucleoside reverse transcriptase inhibitor active against HIV-1, is prescribed in a standard dosage of 25 mg once a day in combination with emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). The aim of this observational study was to characterize the RPV pharmacokinetic profile, to quantify interpatient variability, and to identify potential factors that could influence drug exposure. RPV concentration data were collected from HIV-infected patients as part of routine therapeutic drug monitoring performed in our center (Laboratory of Clinical Pharmacology). A population pharmacokinetic analysis was performed with NONMEM by comparing various structural models. The influence of demographic and clinical covariates, as well as frequent genetic polymorphisms in 5 genes (CYP3A4*22, CYP3A5*3, CYP2C19*2, CYP2C19*17, UGT1A1*28, and UGT1A4*2), on RPV elimination was explored. A total of 325 plasma concentration measurements were obtained from 249 HIV-positive patients. Plasma concentrations ranged from 12 to 255 ng/ml. A one-compartment model with zero-order absorption best characterized RPV pharmacokinetics. The average RPV clearance (CL) was 11.7 liters/h, the average volume of distribution was 401 liters, and the mean absorption time was 4 h. The interinterindividual variability (IIV) for CL was estimated to be 33%. None of the available demographic or genetic covariates showed any influence on RPV pharmacokinetics, but 29% of the patients were predicted to present minimal concentrations below the recently identified target cutoff value of 50 ng/ml. The variability in RPV pharmacokinetics appears to be lower than that for most other antiretroviral drugs. However, under the standard regimen of 25 mg daily, a significant number of patients might be underdosed. It remains to be investigated whether the underexposure has an impact on the development of resistance while patients are on maintenance therapy.

scholarly journals Changing in the profile of a patient with acute coronary syndrome without ST-segment elevation over the years 2015-2020

2021 ◽  
Vol 26 (4) ◽  
pp. 94-98
Author(s):  
O.S. Shchukina
Keyword(s):  
Acute Coronary Syndrome ◽  
Clinical Laboratory ◽  
Clinical Status ◽  
High Sensitivity ◽  
St Segment Elevation ◽  
Coronary Syndrome ◽  
St Segment ◽  
Number Of Patients ◽  
Noteworthy Feature ◽  
Risk Patients

The article represents an analysis of the dynamics of the main demographic, clinical, laboratory, and instrumental investigations, final diagnoses of patients who were hospitalized with a diagnosis of acute coronary syndrome without ST segment elevation. A distinctive feature of the work is the recruitment of patients in the same medical institution for different periods of time, which makes possible to trace the dynamics of the clinical profile of patients in the population of Dnipro, a large industrial center of Ukraine. The prevalence of arterial hypertension, chronic heart failure and previous myocardial infarction remained at the same level. In the 2017-2020’s group compared with the 2015’s group, electrocardiographic  manifestations of acute coronary syndrome without ST-segment elevation upon admission were more often detected. Laboratory indicators such as hemoglobin, creatinine and total cholesterol levels remained the same. Another interesting finding is a statistically significant decrease in the number of patients with a reduced glomerular filtration rate according to MDRD (less than 60 ml/min/1.73 m2) in the 2017-2020’s group compared to patients in 2015’s group, although the clinical course of the disease remained practically unchanged. There was a trend towards a worsening of the clinical status and prognosis, namely, increase in the prevalence of atrial fibrillation and diabetes mellitus, increase in the risk of GRACE, as well as increase in the quantity of verified diagnoses of unstable angina, which is most likely associated with the increased use of high-sensitivity troponin. Noteworthy feature is that increase in the quantity of high-risk patients led to an increase in the mean GRACE score.

Abstract 19818: Coronary CT Angiography for Suspected Acute Coronary Syndrome in the Era of High-Sensitivity Troponins - A Randomized Multicenter Study

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Admir Dedic ◽  
Jeroen Schaap ◽  
Evert Lamfers ◽  
Jeroen Lammers ◽  
Hans Post ◽  
...  
Keyword(s):  
Emergency Department ◽  
Acute Coronary Syndrome ◽  
Ct Angiography ◽  
Primary Endpoint ◽  
Coronary Ct Angiography ◽  
High Sensitivity ◽  
Diagnostic Strategy ◽  
Coronary Syndrome ◽  
Coronary Ct ◽  
Number Of Patients

Introduction: It is uncertain whether a diagnostic strategy supplemented by early coronary CT angiography (CCTA) is superior to contemporary standard optimal care (SOC) encompassing high sensitivity troponins for patients suspected of acute coronary syndrome (ACS) in the emergency department. Hypothesis: To assess whether a diagnostic strategysupplemented by early CCTA improves clinical effectiveness compared to contemporary SOC. Methods: In a prospective, open-label, multicentre, randomized trial, we enrolled patients presenting with symptoms suggestive of an ACSat the emergency department (ED) of five community and two university hospitals in the Netherlands. Exclusion criteria included the need for urgent cardiac catheterization, history of ACS or coronary revascularisation. The primary endpoint was the number of patients identified with significant coronary artery disease requiring revascularization within 30 days. Results: The study population consisted of 500 patients of whom 236 (47%) were women (mean age 54±10 years). There was no difference in the primary endpoint (22 [9%] patients underwent coronary revascularizationwithin 30 days in the CCTA group and 17 [7%] in the SOC group [p= 0·40]). Discharge from ED was not more frequent after CCTA (65% versus 59%, p= 0·16) and length of stay was similar(6·3 hours in both groups, p= 0·80). Direct medical costs were lower in the CCTA group (є337 versus є511, p<0·01). Less outpatient testing was seen with CCTA after index ED visit (10 [4%] versus 26 [10%], p<0·01). There was no difference in incidence of undetected ACS. Conclusions: A diagnostic strategy supplemented by early CCTAis safe, less expensive and averts outpatient testing. However, in the era of high-sensitivity troponins, CCTA does not identify more patients with significant CAD requiring coronary revascularization, nor does CCTAshorten hospital stay or allow for more direct discharge from the ED.

scholarly journals Population Pharmacokinetics of Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

1998 ◽  
Vol 42 (7) ◽  
pp. 1783-1787 ◽  
Author(s):  
Bryan Facca ◽  
Bill Frame ◽  
Steve Triesenberg
Keyword(s):  
Serum Creatinine ◽  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Bacterial Infections ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Beta Lactam ◽  
Serum Samples ◽  
Mixed Effect

ABSTRACT Ceftizoxime is a widely used beta-lactam antimicrobial agent, but pharmacokinetic data for use with clinically ill patients are lacking. We studied the population pharmacokinetics of ceftizoxime in 72 clinically ill patients at a community-based, university-affiliated hospital. A population pharmacokinetic model for ceftizoxime was created by using a prospective observational design. Ceftizoxime was administered by continuous infusion to treat patients with proven or suspected bacterial infections. While the patients were receiving infusions of ceftizoxime, serum samples were collected for pharmacokinetic analysis with the nonlinear mixed-effect modeling program NONMEM. In addition to clearance and volume of distribution, various comorbidities were examined for their influence on the kinetics. All 72 subjects completed the study, and 114 serum samples were collected. Several demographic and comorbidity variables, namely, age, weight, serum creatinine levels, congestive heart failure, and long-term ventilator dependency, had a significant impact on the estimate for ceftizoxime clearance. A mixture model, or two populations for estimation of ceftizoxime clearance, was discovered. One population presented with an additive clearance component of 1.6 liters per h. In addition, a maximizer function for serum creatinine levels was found. In summary, two models for ceftizoxime clearance, mixture and nonmixture, were found and are presented. Clearance for ceftizoxime can be estimated with commonly available clinical information and the models presented. From the clearance estimates, the dose of ceftizoxime to maintain the desired concentration in serum can be determined. Work is needed to validate the model for drug clearance and to evaluate its predictive performance.

scholarly journals Pharmacokinetics of Ceftaroline in Normal Body Weight and Obese (Classes I, II, and III) Healthy Adult Subjects

2015 ◽  
Vol 59 (7) ◽  
pp. 3956-3965 ◽  
Author(s):  
Julie Ann Justo ◽  
Stockton M. Mayer ◽  
Manjunath P. Pai ◽  
Melinda M. Soriano ◽  
Larry H. Danziger ◽  
...  
Keyword(s):  
Body Weight ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Total Body Weight ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Ceftaroline Fosamil ◽  
Plasma And Urine Samples

ABSTRACTThe pharmacokinetic profile of ceftaroline has not been well characterized in obese adults. The purpose of this study was to evaluate the pharmacokinetics of ceftaroline in 32 healthy adult volunteers aged 18 to 50 years in the normal, overweight, and obese body size ranges. Subjects were evenly assigned to 1 of 4 groups based on their body mass index (BMI) and total body weight (TBW) (ranges, 22.1 to 63.5 kg/m2and 50.1 to 179.5 kg, respectively). Subjects in the lower-TBW groups were matched by age, sex, race/ethnicity, and serum creatinine to the upper-BMI groups. Serial plasma and urine samples were collected over 12 h after the start of the infusion, and the concentrations of ceftaroline fosamil (prodrug), ceftaroline, and ceftaroline M-1 (inactive metabolite) were assayed. Noncompartmental and population pharmacokinetic analyses were used to evaluate the data. The mean plasma ceftaroline maximum concentration and area under the curve were ca. 30% lower in subjects with a BMI of ≥40 kg/m2compared to those <30 kg/m2. A five-compartment pharmacokinetic model with zero-order infusion and first-order elimination optimally described the plasma concentration-time profiles of the prodrug and ceftaroline. Estimated creatinine clearance (eCLCR) and TBW best explained ceftaroline clearance and volume of distribution, respectively. Although lower ceftaroline plasma concentrations were observed in obese subjects, Monte Carlo simulations suggest the probability of target attainment is ≥90% when the MIC is ≤1 μg/ml irrespective of TBW or eCLCR. No dosage adjustment for ceftaroline appears to be necessary based on TBW alone in adults with comparable eCLCR. Confirmation of these findings in infected obese patients is necessary to validate these findings in healthy volunteers. (This study has been registered at ClinicalTrials.gov under registration no. NCT01648127.)

scholarly journals Plasma and Intracellular Population Pharmacokinetic Analysis of Tenofovir in HIV-1-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5294-5299 ◽  
Author(s):  
Gautam Baheti ◽  
Jennifer J. Kiser ◽  
Peter L. Havens ◽  
Courtney V. Fletcher
Keyword(s):  
Rate Constant ◽  
Sequential Analysis ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Distribution Volume ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Response Model ◽  
Indirect Response Model ◽  
Indirect Response

ABSTRACTThe relationships among the dose of tenofovir disoproxil fumarate (TDF), tenofovir (TFV) plasma concentrations, and intracellular TFV diphosphate (TFV-DP) concentrations are poorly understood. Our objective was to characterize TFV and TFV-DP relationships. Data were pooled from two studies in HIV-infected persons (n= 55) on stable antiretroviral therapy. TFV and TFV-DP were measured with validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) methods. Nonlinear mixed effects modeling (NONMEM 7) was used to develop the population model and explore the influence of covariates on TFV. A sequential analysis approach was utilized. A two-compartment model with first-order absorption best described TFV PK (FOCEI). An indirect stimulation of response model best described TFV-DP, where formation of TFV-DP was driven by plasma TFV concentration. Final plasma population estimates were as follows: absorption rate constant, 1.03 h−1; apparent clearance (CL/F), 42 liters/h (33.5% interindividual variability [IIV]); intercompartment clearance, 181 liters/h; apparent central distribution volume (Vc/F), 273 liters (64.8% IIV); and apparent peripheral distribution volume (Vp/F), 440 liters (46.5% IIV). Creatinine clearance was the most significant covariate on CL/F and Vc/F. The correlation between CL/F and Vc/F was 0.553. The indirect response model for TFV-DP resulted in estimates of the maximal intracellular concentration (Emax), the TFV concentration producing 50% ofEmax(EC50), and the intracellular elimination rate constant (kout) of 300 fmol/106cells (82% IIV), 100 ng/ml (106% IIV), and 0.008 h−1, respectively. The estimatedkoutgave an 87-h TFV-DP half-life. A predictive check assessment indicated satisfactory model performance. This model links formation of TFV-DP with plasma TFV concentrations and should facilitate more informed investigations of TFV clinical pharmacology.

scholarly journals Residual Dyslipidemia Leads to Unfavorable Outcomes in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention

2016 ◽  
Vol 2016 ◽  
pp. 1-5
Author(s):  
Bin Que ◽  
Chunmei Wang ◽  
Hui Ai ◽  
Xinyong Zhang ◽  
Mei Wang ◽  
...  
Keyword(s):  
Percutaneous Coronary Intervention ◽  
Acute Coronary Syndrome ◽  
Cox Regression ◽  
Plasma Concentrations ◽  
Coronary Intervention ◽  
High Rate ◽  
Cox Regression Analysis ◽  
Coronary Syndrome ◽  
Percutaneous Coronary ◽  
Low Hdl

Background. The present study aimed to evaluate the prevalence and prognosis of residual lipid abnormalities in statin-treated acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI).Subjects and Methods. A total of 3,047 ACS patients who underwent PCI and received statin therapy were included. Plasma concentrations of LDL-C, HDL-C, and TG were measured. For the follow-up study, major adverse cardiovascular cerebrovascular events (MACCE; including total death, cardiovascular death, myocardial infarction, and revascularization) were documented.Results. A total of 93.14% of all individuals were followed up for 18.1 months (range, 0–29.3 months). Of all 3,047 patients, those with a suboptimal goal were 67.75%, 85.85%, and 33.64% for LDL-C, HDL-C, and TG levels, respectively. Multiple Cox regression analysis revealed there were significant increases in cumulative MACCE of 41% (HR = 1.41, 95% CI [1.09–1.82],p=0.008), and revascularization of 48% (HR = 1.48, 95% CI [1.10–1.99],p=0.01) in low HDL-C patients with ACS after PCI, but not the high TG group at the end of study.Conclusions. Our results showed there is high rate of dyslipidemia in Chinese ACS patients after PCI. Importantly, low HDL-C but not high TG levels are associated with higher MACCE and revascularization rates in ACS patients after PCI.

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