scholarly journals Clinical Application of Vancomycin PPK Model in Patients with Neutropenia

2021 ◽  
Author(s):  
Xiangjun Fu ◽  
Li Huang ◽  
Li Guo ◽  
Liangmo Lin
Keyword(s):  
Clinical Application ◽  
Compartment Model ◽  
Empiric Therapy ◽  
Model Group ◽  
Target Concentration ◽  
Mixed Effect ◽  
Model Study ◽  
Nonlinear Mixed Effect ◽  
Two Compartment Model ◽  
Stability And Accuracy

Abstract Background: To explore the clinical application of a population pharmacokinetics (PPK) model of vancomycin in patients with hematological diseases who developed neutropenia.Methods: Patients with neutropenia treated at the Department of Hematology in our hospital were included in the PPK model study. A nonlinear mixed effect modeling approach (NONMEM) was used to establish the PPK model of those patients. Monte Carlo simulation was also carried out. A total of 64 patients were divided into model group and non-model group for clinical application research. The model group was given the first dose of 1g q8h, and the non-model group was given 1g q12h as the empiric therapy; the follow-up dose adjustment was made according to the concentration results.Results: This two-compartment model showed good stability and accuracy. The average concentrations in the model group and the non-model group were significantly different, i.e., 13.45±4.07 μg/ml, 60.71% reaching the target concentration vs. 9.85±3.76 μg/ml, 27.78% reaching the target concentration, respectively (all P<0.05). This suggested that for patients with neutropenia and CLCR≥90 ml/min/1.73m2, the first dose of 1g q8h may help to reach the target concentration as soon as possible.Conclusions: Our PPK model of vancomycin in patients with hematologic diseases who developed neutropenia can be used to realize the individualized application of vancomycin in this population.

scholarly journals Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients

2018 ◽  
Vol 47 (04) ◽  
pp. 621-629 ◽  
Author(s):  
Lisette Schütte ◽  
Reinier van Hest ◽  
Sara Stoof ◽  
Frank Leebeek ◽  
Marjon Cnossen ◽  
...  
Keyword(s):  
Compartment Model ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Small Subset ◽  
Population Pharmacokinetic ◽  
Haemophilia A ◽  
Mixed Effect ◽  
Large Variability ◽  
Nonlinear Mixed Effect ◽  
Two Compartment Model

Background Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict. Objectives Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling. Patients and Methods Retrospective data of 128 nonsevere HA patients (age 7–75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reproducibility of FVIII:C response was defined as less than 25% difference in peak FVIII:C between administrations. Results A total of 623 FVIII:C measurements from 142 desmopressin administrations were available; 14 patients had received two administrations at different occasions. The FVIII:C time profile was best described by a two-compartment model with first-order absorption and elimination. Interindividual variability of the estimated baseline FVIII:C, central volume of distribution and clearance were 37, 43 and 50%, respectively. The most recently measured FVIII:C (FVIII-recent) was significantly associated with FVIII:C response to desmopressin (p < 0.001). Desmopressin administration resulted in an absolute FVIII:C increase of 0.47 IU/mL (median, interquartile range: 0.32–0.65 IU/mL, n = 142). FVIII:C response was reproducible in 6 out of 14 patients receiving two desmopressin administrations. Conclusion FVIII:C response to desmopressin in nonsevere HA patients was adequately described by a population PK model. Large variability in FVIII:C response was observed, which could only partially be explained by FVIII-recent. FVIII:C response was not reproducible in a small subset of patients. Therefore, monitoring FVIII:C around surgeries or bleeding might be considered. Research is needed to study this further.

scholarly journals Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

2015 ◽  
Vol 59 (7) ◽  
pp. 3935-3943 ◽  
Author(s):  
Kevin M. Watt ◽  
Daniel Gonzalez ◽  
Daniel K. Benjamin ◽  
Kim L. R. Brouwer ◽  
Kelly C. Wade ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effect ◽  
Final Model ◽  
Content Type ◽  
Membrane Oxygenation ◽  
Nonlinear Mixed Effect ◽  
Nonlinear Mixed Effect Modeling ◽  
Drug Pharmacokinetics

ABSTRACTCandidainfections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO onVas follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)−0.29× exp(ηCL) andV(in liters) = 0.93 × weight × 1.4ECMO× exp(ηV). The fluconazoleVwas increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.

scholarly journals Population Pharmacokinetic/Pharmacogenetic Model for Optimization of Efavirenz Therapy in Caucasian HIV-Infected Patients

2011 ◽  
Vol 55 (11) ◽  
pp. 5314-5324 ◽  
Author(s):  
Almudena Sánchez ◽  
Salvador Cabrera ◽  
Dolores Santos ◽  
M. Paz Valverde ◽  
Aurelio Fuertes ◽  
...  
Keyword(s):  
High Performance ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Nucleotide Polymorphisms ◽  
Mixed Effect ◽  
Factors Affecting ◽  
Nonlinear Mixed Effect ◽  
Study Population ◽  
Major Factors

ABSTRACTDespite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C→T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 − 0.00279·GGT)·0.602CYP2B6*6 [G/T]·0.354CYP2B6*6 [T/T]·0.793MRP4 1497C→T, where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C→T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

Pharmacokinetics/Pharmacodynamics of caspofungin in plasma and peritoneal fluid of liver transplant recipients

2021 ◽  
Author(s):  
Claire Pressiat ◽  
Nawel Ait-Ammar ◽  
Matthieu Daniel ◽  
Anne Hulin ◽  
Françoise Botterel ◽  
...  
Keyword(s):  
Liver Transplant ◽  
Peritoneal Fluid ◽  
Compartment Model ◽  
Transplant Recipients ◽  
Mixed Effect ◽  
First Order ◽  
Transplant Patients ◽  
Two Compartment Model ◽  
Dosing Regimens ◽  
Liver Transplant Recipients

Background: The weaker diffusion of echinocandins in the peritoneal fluid (PF) could promote Candida resistant isolates. The aim of this study was to analyse the pharmacokinetics/pharmacodynamics (PK/PD) of caspofungin in plasma and PF of liver transplant recipients. Methods: Liver transplant patients received caspofungin as postoperative prophylaxis. Caspofungin concentrations were quantified in plasma and in PF on Days 1, 3 and 8. Data were analysed using non-linear mixed-effect modelling and Monte Carlo simulations. Area under curve (AUC) in plasma and PF were simulated under three dosing regimens. Probabilities of target attainment (PTA) were calculated using fAUC 0-24 /minimal inhibitory concentration (MIC) ratios with MICs ranging from 0.008 to 8 mg/litre. All the patients included were monitored weekly for Candida colonisation and for Candida infections. Results: Twenty patients were included. Median daily dose of caspofungin was 0.81 mg/kg. Plasma (n=395) and peritoneal (n=50) concentrations at steady state were available. A two-compartment model with first-order absorption and elimination was described. Our two-compartment model with first-order absorption and elimination model produced an effective PK/PD relationship in plasma, achieving a PTA ≥90% and MIC ranging from 0.008 to 0.12 mg/L for C. albicans and glabrata . In PF, PTAs at D8 were only optimal for a MIC of 0.008 in patients weighing 60 kg under the three dosing regimens. Among the 16 patients colonized, all MIC values were below the maximal concentration (Cmax) in plasma but not in PF. Conclusion: Peritoneal concentrations of caspofungin were low. Simulations showed that the PTA for Candida spp. in PF were not optimal, that might suggesting a potential risk of resistance.

scholarly journals Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

2006 ◽  
Vol 50 (11) ◽  
pp. 3548-3555 ◽  
Author(s):  
Vincent Jullien ◽  
Saïk Urien ◽  
Déborah Hirt ◽  
Constance Delaugerre ◽  
Elisabeth Rey ◽  
...  
Keyword(s):  
Population Analysis ◽  
Combined Treatment ◽  
Elimination Rate ◽  
Compartment Model ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect ◽  
Nonlinear Mixed Effect Modeling ◽  
Age And Sex

ABSTRACT The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

Population pharmacokinetics and dosing simulations of amoxicillin in obese adults receiving co-amoxiclav

2020 ◽  
Vol 75 (12) ◽  
pp. 3611-3618
Author(s):  
G Mellon ◽  
K Hammas ◽  
C Burdet ◽  
X Duval ◽  
C Carette ◽  
...  
Keyword(s):  
Compartment Model ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Mixed Effect ◽  
Mean Values ◽  
Two Compartment Model ◽  
Amoxicillin Clavulanate ◽  
Dosing Regimens ◽  
Obese Subjects

Abstract Background Pneumonia, skin and soft tissue infections are more frequent in obese patients and are most often treated by co-amoxiclav, using similar dosing regimens to those used for non-obese subjects. No data are available on amoxicillin pharmacokinetics among obese subjects receiving co-amoxiclav. Materials and methods Prospective, single-centre, open-label, non-randomized, crossover pharmacokinetic trial having enrolled obese otherwise healthy adult subjects. A first dose of co-amoxiclav (amoxicillin/clavulanate 1000/200 mg) was infused IV over 30 min, followed by a second dose (1000/125 mg) administered orally, separated by a washout period of ≥24 h. We assayed concentrations of amoxicillin by a validated ultra HPLC–tandem MS technique. We estimated population pharmacokinetic parameters of amoxicillin by non-linear mixed-effect modelling using the SAEM algorithm developed by Monolix. Results Twenty-seven subjects were included in the IV study, with 24 included in the oral part of the study. Median body weight and BMI were 109.3 kg and 40.6 kg/m2, respectively. Amoxicillin pharmacokinetics were best described by a two-compartment model with first-order elimination. Mean values for clearance, central volume, intercompartmental clearance and peripheral volume were, respectively, 14.6 L/h, 9.0 L, 4.2 L/h and 6.4 L for amoxicillin. Oral bioavailability of amoxicillin was 79.7%. Amoxicillin Cmax after oral administration significantly reduced with weight (P = 0.013). Dosing simulations for amoxicillin predicted that most of the population will achieve the pharmacodynamic target of fT&gt;MIC ≥40% with the regimen of co-amoxiclav 1000/200 mg (IV) or 1000/125 mg (oral) q8h for MICs titrated up to 0.5 mg/L (IV) and 1 mg/L (oral). Conclusions Pharmacokinetic/pharmacodynamic goals for amoxicillin can be obtained in obese subjects.

scholarly journals P72 Maturation of sildenafil clearance in prematurely born infants with BPD associated pulmonary hypertension

2019 ◽  
Vol 104 (6) ◽  
pp. e47.1-e47
Author(s):  
H Nikrawesh ◽  
AGJ Engbers ◽  
S Völler ◽  
SHP Simons ◽  
BCP Koch ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Limited Information ◽  
Mixed Effect ◽  
Time Profiles ◽  
Nonlinear Mixed Effect ◽  
Postmenstrual Age ◽  
Oral Doses ◽  
Prematurely Born Infants

BackgroundSildenafil is used as an off-label treatment for bronchopulmonary dysplasia (BPD) associated pulmonary hypertension in prematurely born infants. As there is only limited information on the pharmacokinetics (PK) of sildenafil in this population, the aim of this study is to investigate the PK of sildenafil in prematurely born infants with BPD associated pulmonary hypertension.MethodIn this multicentre study, a population PK model for sildenafil in prematurely born infants was developed based on samples obtained using opportunistic sampling during clinical use of sildenafil. Data of seven subjects (42 plasma samples) were analysed by nonlinear mixed-effect modelling (NONMEM®7.3). Median (range) gestational age (GA) was 26.1 (24.1–27.6) weeks, current bodyweight 1960 (632–3157) grams, birthweight 635 (465–1125) grams and postnatal age (PNA) at start of therapy 64.9 (10.9–89) days. The median (range) treatment duration was 4.9 (1.6–13.1) weeks, with six subjects receiving oral doses of median 2.6 mg/kg/day (1.5–5.3) in three doses and one subject receiving oral and intravenous doses of 6.7 mg/kg/day in two doses.ResultsThe plasma concentration time profiles of sildenafil were best described by a one compartment model. Clearance (CL) and volume of distribution (Vd) for a child with a PNA of 64.9 days and bodyweight of 1.96 kg was 4.42 L/h ((RSE) 11%) and 29.5 L (32%), respectively. PNA was found to significantly influence CL, resulting in an increase of 10.7% in a week, and 43% in a month for a 65-day old infant. No other covariates (i.e. bodyweight, birthweight, GA, postmenstrual age and sex) were identified for CL or Vd.ConclusionIn this PK study, we characterised the pharmacokinetics of sildenafil in prematurely born infants and found that clearance increases with PNA. Due to the limited sample size in this study, further research in a larger population is needed to extend these findings.Disclosure(s)Nothing to disclose

scholarly journals Pharmacokinetics of Hydroxychloroquine and Its Clinical Implications in Chemoprophylaxis against Malaria Caused by Plasmodium vivax

2009 ◽  
Vol 53 (4) ◽  
pp. 1468-1475 ◽  
Author(s):  
Hyeong-Seok Lim ◽  
Jeong-Soo Im ◽  
Joo-Youn Cho ◽  
Kyun-Seop Bae ◽  
Terry A. Klein ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Vivax Malaria ◽  
Prediction Interval ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Republic Of Korea ◽  
Mixed Effect ◽  
Two Compartment Model ◽  
Effect Of Treatment ◽  
The Republic

ABSTRACT Hydroxychloroquine (HCQ) is an antimalarial drug used as chemoprophylaxis against malaria caused by Plasmodium vivax in the Republic of Korea Army (ROKA). In this study, we evaluated the pharmacokinetics (PK) of HCQ and its metabolites and the relationship between the PK of HCQ and the effect of treatment of HCQ on vivax malaria in South Koreans. Three PK studies of HCQ were conducted with 91 healthy subjects and patients with vivax malaria. Plasma concentrations were analyzed by noncompartmental and mixed-effect modeling approaches. A two-compartment model with first-order absorption best described the data. The clearance and the central and peripheral volumes of distribution were 15.5 liters/h, 733 liters, and 1,630 liters, respectively. We measured the plasma concentrations of HCQ in patients with prophylactic failure of HCQ and compared them with the prediction intervals of the simulated concentrations for HCQ from the final PK model built in this study. In 71% of the patients with prophylactic failure, the plasma concentrations of HCQ were below the lower bounds of the 95% prediction interval, while only 8% of them showed higher levels than the upper bounds of the 95% prediction interval. We report that a significant cause of prophylactic failure among the individuals in ROKA was ascribed to plasma concentrations of HCQ lower than those predicted by the PK model. However, prophylactic failure despite sufficient plasma concentrations of HCQ was confirmed in several individuals, warranting continued surveillance to monitor changes in the HCQ susceptibility of Plasmodium vivax in the Republic of Korea.

Two-Compartment Model of Cholesterol Kinetics for Establishment of Treatment Strategy of LDL Apheresis in Nephrotic Hypercholesterolemia

1994 ◽  
Vol 12 (6) ◽  
pp. 317-326 ◽  
Author(s):  
Masatomo Yashiro ◽  
Eri Muso ◽  
Munehiro Matsushima ◽  
Ryoichi Nagura ◽  
Kenji Sawanishi ◽  
...  
Keyword(s):  
Treatment Strategy ◽  
Compartment Model ◽  
Ldl Apheresis ◽  
Two Compartment Model
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