scholarly journals P109 Optimal dosing regimen of caspofungin in children: milligram per kilogram or milligram per square meter?

2019 ◽  
Vol 104 (6) ◽  
pp. e63.2-e63
Author(s):  
X-M Yang ◽  
S Leroux ◽  
T Storme ◽  
D-L Zhang ◽  
T Adam de Beaumais ◽  
...  
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Population Pharmacokinetics ◽  
Surface Area ◽  
Body Surface ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Candida Spp ◽  
Optimal Dosing

BackgroundCaspofungin is the first echinocandin to be used as a first-line antifungal agent for Candida spp. infections in febrile, neutropenic adult and paediatric patients. To date, the optimal dosing of capofungin in children has not been determined. We evaluated the population pharmacokinetics of caspofungin in children (2–12 years old) and defined an appropriate dose in order to optimize caspofungin treatment in this vulnerable population.MethodsBlood samples were collected from 48 children treated with caspofungin and drug concentrations were quantified by HPLC-MS. Population pharmacokinetic analysis and Monte-Carlo simulation were performed using NONMEM softwareResultsData from 48 children was available for population pharmacokinetic analysis. A two-compartment model with first-order elimination had the best fit with the data. Subsequent covariate analysis demonstrated that body surface area had a significant correlation with caspofungin pharmacokinetics compared to body weight. Monte Carlo simulation demonstrated that >90% of a simulated paediatric population (age range, 2–12 years) treated with a loading dose of 70 mg/m2 followed by a 50 mg/m2 maintenance dose once daily would reach a minimum inhibitory concentration of 1 µg/mL, the proposed susceptibility breakpoint for caspofungin against Candida spp.ConclusionThe population pharmacokinetics of caspofungin was evaluated and revealed that adjustment of caspofungin based on body surface area is most appropriate for paediatric use.Disclosure(s)Nothing to disclose

scholarly journals Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

2015 ◽  
Vol 60 (1) ◽  
pp. 206-214 ◽  
Author(s):  
Mohd H. Abdul-Aziz ◽  
Azrin N. Abd Rahman ◽  
Mohd-Basri Mat-Nor ◽  
Helmi Sulaiman ◽  
Steven C. Wallis ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Monte Carlo ◽  
Intensive Care ◽  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic

ABSTRACTDoripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CLCR), such that a 30-ml/min increase in the estimated CLCRwould increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CLCRof 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CLCRof >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.

scholarly journals Rational Dose Selection for a Nonnucleoside Reverse Transcriptase Inhibitor through Use of Population Pharmacokinetic Modeling and Monte Carlo Simulation

2002 ◽  
Vol 46 (3) ◽  
pp. 913-916 ◽  
Author(s):  
G. L. Drusano ◽  
K. H. P. Moore ◽  
J. P. Kleim ◽  
W. Prince ◽  
A. Bye
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Population Pharmacokinetic Analysis ◽  
Free Drug ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Double Blind ◽  
Population Pharmacokinetic Modeling ◽  
Rational Dose ◽  
Trough Concentrations

ABSTRACT In order to choose a rational dose for GW 420867X, we first set a goal of therapy. We hypothesized that, for optimal antiretroviral activity, the trough free drug concentration should remain above the 90% effective concentration (EC90) of human immunodeficiency virus type 1. We performed population pharmacokinetic analysis on three different doses of GW 420867X (50, 100, and 200 mg). Monte Carlo simulation was performed, assuming a log-normal distribution for 1,000 simulated subjects for each dose, and was repeated three times. The trough concentrations were divided by 76 to account for protein binding and for the difference between EC50 and EC90. We then determined the fraction of the simulated population whose free drug trough concentrations would exceed an EC90 over a broad range of values. The target attainment for all three doses exceeded 95% out to a starting EC50 of 10 nM. For 16 viral isolates, the EC50 range encountered for GW 420867X did not exceed 8 nM, implying that the three doses could not be differentiated by effect in a clinical trial in naive patients. This prediction was shown to be correct in a randomized, double-blind trial with 1 week of monotherapy with GW 420867X.

scholarly journals Population Pharmacokinetics of Continuous-Infusion Meropenem in Febrile Neutropenic Patients with Hematologic Malignancies: Dosing Strategies for Optimizing Empirical Treatment against Enterobacterales and P. aeruginosa

Pharmaceutics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 785
Author(s):  
Pier Giorgio Cojutti ◽  
Anna Candoni ◽  
Davide Lazzarotto ◽  
Carla Filì ◽  
Maria Zannier ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Monte Carlo Simulations ◽  
Continuous Infusion ◽  
Hematologic Malignancies ◽  
Population Pharmacokinetic Analysis ◽  
Empirical Treatment ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Strategies ◽  
Neutropenic Patients

A population pharmacokinetic analysis of continuous infusion (CI) meropenem was conducted in a prospective cohort of febrile neutropenic (FN) patients with hematologic malignancies. A non-parametric approach with Pmetrics was used for pharmacokinetic analysis and covariate evaluation. Monte Carlo simulations were performed for identifying the most appropriate dosages for empirical treatment against common Enterobacterales and P. aeruginosa. The probability of target attainment (PTA) of steady-state meropenem concentration (Css)-to-minimum inhibitory concentration (MIC) ratio (Css/MIC) ≥1 and ≥4 at the European Committee on Antimicrobial Susceptibility Testing (EUCAST) clinical breakpoint of 2 mg/L were calculated. Cumulative fraction of response (CFR) against Enterobacterales and P. aeruginosa were assessed as well. PTAs and CFRs ≥ 90% were considered optimal. A total of 61 patients with 178 meropenem Css were included. Creatinine clearance (CLCR) was the only covariate associated with meropenem clearance. Monte Carlo simulations showed that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may grant optimal PTAs of Css/MIC ≥4 at the EUCAST clinical breakpoint. Optimal CFRs may be granted with these dosages against the Enterobacterales at Css/MIC ≥ 4 and against P. aeruginosa at Css/MIC ≥ 1. When dealing against P. aeruginosa at Css/MIC ≥ 4, only a dosage of 1.5 g q6h by CI may grant quasi-optimal CFR (around 80–87%). In conclusion, our findings suggest that dosages of meropenem ranging between 1 g q8h and 1.25 g q6h by CI may maximize empirical treatment against Enterobacterales and P. aeruginosa among FN patients with hematologic malignancies having different degree of renal function.

scholarly journals Population Pharmacokinetics of Ciprofloxacin in Neonates and Young Infants Less than Three Months of Age

2014 ◽  
Vol 58 (11) ◽  
pp. 6572-6580 ◽  
Author(s):  
Wei Zhao ◽  
Helen Hill ◽  
Chantal Le Guellec ◽  
Tim Neal ◽  
Sarah Mahoney ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Newborn Infants ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Dosing Regimen ◽  
Creatinine Concentration ◽  
Young Infants

ABSTRACTCiprofloxacin is used in neonates with suspected or documented Gram-negative serious infections. Currently, its use is off-label partly because of lack of pharmacokinetic studies. Within the FP7 EU project TINN (Treat Infection in NeoNates), our aim was to evaluate the population pharmacokinetics of ciprofloxacin in neonates and young infants <3 months of age and define the appropriate dose in order to optimize ciprofloxacin treatment in this vulnerable population. Blood samples were collected from neonates treated with ciprofloxacin and concentrations were quantified by high-pressure liquid chromatography–mass spectrometry. Population pharmacokinetic analysis was performed using NONMEM software. The data from 60 newborn infants (postmenstrual age [PMA] range, 24.9 to 47.9 weeks) were available for population pharmacokinetic analysis. A two-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that gestational age, postnatal age, current weight, serum creatinine concentration, and use of inotropes had a significant impact on ciprofloxacin pharmacokinetics. Monte Carlo simulation demonstrated that 90% of hypothetical newborns with a PMA of <34 weeks treated with 7.5 mg/kg twice daily and 84% of newborns with a PMA ≥34 weeks and young infants receiving 12.5 mg/kg twice daily would reach the AUC/MIC target of 125, using the standard EUCAST MIC susceptibility breakpoint of 0.5 mg/liter. The associated risks of overdose for the proposed dosing regimen were <8%. The population pharmacokinetics of ciprofloxacin was evaluated in neonates and young infants <3 months old, and a dosing regimen was established based on simulation.

scholarly journals Bone Penetration of Amoxicillin and Clavulanic Acid Evaluated by Population Pharmacokinetics and Monte Carlo Simulation

2009 ◽  
Vol 53 (6) ◽  
pp. 2569-2578 ◽  
Author(s):  
Cornelia B. Landersdorfer ◽  
Martina Kinzig ◽  
Jürgen B. Bulitta ◽  
Friedrich F. Hennig ◽  
Ulrike Holzgrabe ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Cortical Bone ◽  
Population Pharmacokinetics ◽  
Clavulanic Acid ◽  
Cancellous Bone ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Bone Infections ◽  
Drug Concentrations ◽  
Amoxicillin Clavulanic Acid

ABSTRACT Amoxicillin (amoxicilline)-clavulanic acid has promising activity against pathogens that cause bone infections. We present the first evaluation of the bone penetration of a beta-lactam by population pharmacokinetics and pharmacodynamic profiling via Monte Carlo simulations. Twenty uninfected patients undergoing total hip replacement received a single intravenous infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid before surgery. Blood and bone specimens were collected. Bone samples were pulverized under liquid nitrogen with a cryogenic mill, including an internal standard. The drug concentrations in serum and total bone were analyzed by liquid chromatography-tandem mass spectrometry. We used NONMEM and S-ADAPT for population pharmacokinetic analysis and a target time of the non-protein-bound drug concentration above the MIC for ≥50% of the dosing interval for near-maximal bactericidal activity in serum. The median of the ratio of the area under the curve (AUC) for bone/AUC for serum was 20% (10th to 90th percentile for between-subject variability [variability], 16 to 25%) in cortical bone and 18% (variability, 11 to 29%) in cancellous bone for amoxicillin and 15% (variability, 11 to 21%) in cortical bone and 10% (variability, 5.1 to 21%) in cancellous bone for clavulanic acid. Analysis in S-ADAPT yielded similar results. The equilibration half-lives between serum and bone were 12 min for amoxicillin and 14 min for clavulanic acid. For a 30-min infusion of 2,000 mg/200 mg amoxicillin-clavulanic acid every 4 h, amoxicillin achieved robust (≥90%) probabilities of target attainment (PTAs) for MICs of ≤12 mg/liter in serum and 2 to 3 mg/liter in bone and population PTAs above 95% against methicillin-susceptible Staphylococcus aureus in bone and serum. The AUC of amoxicillin-clavulanic acid was 5 to 10 times lower in bone than in serum, and amoxicillin-clavulanic acid achieved a rapid equilibrium and favorable population PTAs against pathogens commonly encountered in bone infections.

scholarly journals Population Pharmacokinetics and Dosing Optimization of Ceftazidime in Infants

2018 ◽  
Vol 62 (4) ◽  
Author(s):  
Zhong-Ren Shi ◽  
Xing-Kai Chen ◽  
Li-Yuan Tian ◽  
Ya-Kun Wang ◽  
Gu-Ying Zhang ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
High Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Generation Cephalosporin ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Dosing Regimen ◽  
Age Range

ABSTRACT Ceftazidime, a third-generation cephalosporin, can be used for the treatment of adults and children with infections due to susceptible bacteria. To date, the pediatric pharmacokinetic data are limited in infants, and therefore we aimed to evaluate the population pharmacokinetics of ceftazidime in infants and to define the appropriate dose to optimize ceftazidime treatment. Blood samples were collected from children treated with ceftazidime, and concentrations of the drug were quantified by high-performance liquid chromatography with UV detection (HPLC-UV). A population pharmacokinetic analysis was performed using NONMEM software ( version 7.2.0). Fifty-one infants ( age range, 0.1 to 2.0 years ) were included. Sparse pharmacokinetic samples ( n = 90 ) were available for analysis. A one-compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that body weight and creatinine clearance (CL CR ) were significant covariates influencing ceftazidime clearance. Monte Carlo simulation demonstrated that the currently used dosing regimen of 50 mg / kg twice daily was associated with a high risk of underdosing in infants. In order to reach the target of 70% of the time that the free antimicrobial drug concentration exceeds the MIC ( fT >MIC ), 25 mg/kg every 8 h (q8h) and 50 mg/kg q8h were required for MICs of 4 and 8 mg/liter, respectively. The population pharmacokinetic characteristics of ceftazidime were evaluated in infants. An evidence-based dosing regimen was established based on simulation.

scholarly journals Pharmacodynamic Profiling of Piperacillin in the Presence of Tazobactam in Patients through the Use of Population Pharmacokinetic Models and Monte Carlo Simulation

2004 ◽  
Vol 48 (12) ◽  
pp. 4718-4724 ◽  
Author(s):  
Thomas P. Lodise ◽  
Ben Lomaestro ◽  
Keith A. Rodvold ◽  
Larry H. Danziger ◽  
George L. Drusano
Keyword(s):  
Monte Carlo Simulation ◽  
Monte Carlo ◽  
Linear Model ◽  
Pharmacokinetic Model ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Raw Data ◽  
Dosing Interval ◽  
Pharmacodynamic Profile

ABSTRACT The primary objectives of this analysis were to determine which pharmacokinetic model most accurately describes the elimination pathways for piperacillin in the presence of tazobactam through population pharmacokinetic modeling and to characterize its pharmacodynamic profile. Once the optimal pharmacokinetic model was identified, Monte Carlo simulation of 10,000 subjects with ADAPT II was performed to estimate the probability of attaining a target free-piperacillin concentration greater than the MIC for 50% of the dosing interval for 3.375 g every 6 h or every 4 h given as a 0.5-h infusion at each MIC between 0.25 and 32 μg/ml. In the population pharmacokinetic analysis, measurements of bias and precision, observed-predicted plots, and r 2 values were highly acceptable for all three models and all three models were appropriate candidates for the Monte Carlo simulation evaluation. Visual comparison of the distribution of the piperacillin concentrations at the pharmacodynamic endpoint—h 3 concentrations of a 6-h dosing interval—between the simulated populations and raw data revealed that the linear model was most reflective of the raw data at the pharmacodynamic endpoint, and the linear model was therefore selected for the target attainment analysis. In the target attainment analysis, administration of 3 g of piperacillin every 6 h resulted in a robust target attainment rate that exceeded 95% for MICs of ≤8 mg/liter. The 4-h piperacillin administration interval had a superior pharmacodynamic profile and provided target attainment rates exceeding 95% for MICs of ≤16 mg/liter. This study indicates that piperacillin-tazobactam should have utility for empirical therapy of hospital-onset infections.

scholarly journals Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

2005 ◽  
Vol 49 (6) ◽  
pp. 2504-2506 ◽  
Author(s):  
Edmund V. Capparelli ◽  
Scott L. Letendre ◽  
Ronald J. Ellis ◽  
Parul Patel ◽  
Diane Holland ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Cerebrospinal Fluid ◽  
Population Pharmacokinetics ◽  
Virus Replication ◽  
Dose Interval ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Human Immunodeficiency Virus Replication ◽  
Population Pharmacokinetic ◽  
Immunodeficiency Virus

ABSTRACT The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.

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