scholarly journals Optimal Dosing of Ceftriaxone in Infants Based on a Developmental Population Pharmacokinetic-Pharmacodynamic Analysis

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Ya-Kun Wang ◽  
Yue-E Wu ◽  
Xue Li ◽  
Li-Yuan Tian ◽  
Muhammad Wasim Khan ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Sampling Strategy ◽  
Optimal Dose ◽  
Community Acquired Pneumonia ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Evidence Based ◽  
Open Label ◽  
Large Variability ◽  
Pharmacodynamic Analysis

ABSTRACT Ceftriaxone is a third-generation cephalosporin used to treat infants with community-acquired pneumonia. Currently, there is a large variability in the amount of ceftriaxone used for this purpose in this particular age group, and an evidence-based optimal dose is still unavailable. Therefore, we investigated the population pharmacokinetics of ceftriaxone in infants and performed a developmental pharmacokinetic-pharmacodynamic analysis to determine the optimal dose of ceftriaxone for the treatment of infants with community-acquired pneumonia. A prospective, open-label pharmacokinetic study of ceftriaxone was conducted in infants (between 1 month and 2 years of age), adopting an opportunistic sampling strategy to collect blood samples and applying high-performance liquid chromatography to quantify ceftriaxone concentrations. Developmental population pharmacokinetic-pharmacodynamic analysis was conducted using nonlinear mixed effects modeling (NONMEM) software. Sixty-six infants were included, and 169 samples were available for pharmacokinetic analysis. A one-compartment model with first-order elimination matched the data best. Covariate analysis elucidated that age and weight significantly affected ceftriaxone pharmacokinetics. According to the results of a Monte Carlo simulation, with a pharmacokinetic-pharmacodynamic target of a free drug concentration above the MIC during 70% of the dosing interval (70% fT>MIC), regimens of 20 mg/kg of body weight twice daily for infants under 1 year of age and 30 mg/kg twice daily for those older than 1 year of age were suggested. The population pharmacokinetics of ceftriaxone were established in infants, and evidence-based dosing regimens for community-acquired pneumonia were suggested based on developmental pharmacokinetics-pharmacodynamics.

Developmental population pharmacokinetics–pharmacodynamics and dosing optimization of cefoperazone in children

2020 ◽  
Vol 75 (7) ◽  
pp. 1917-1924
Author(s):  
Hai-Yan Shi ◽  
Kai Wang ◽  
Rong-Hua Wang ◽  
Yue-E Wu ◽  
Bo-Hao Tang ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Open Label ◽  
Treatment Target ◽  
Two Compartment Model ◽  
Pharmacodynamic Analysis ◽  
Dosing Optimization

Abstract Objectives To evaluate the population pharmacokinetics of cefoperazone in children and establish an evidence-based dosing regimen using a developmental pharmacokinetic–pharmacodynamic approach in order to optimize cefoperazone treatment. Methods A model-based, open-label, opportunistic-sampling pharmacokinetic study was conducted in China. Blood samples from 99 cefoperazone-treated children were collected and quantified by HPLC/MS. NONMEM software was used for population pharmacokinetic–pharmacodynamic analysis. This study was registered at ClinicalTrials.gov (NCT03113344). Results A two-compartment model with first-order elimination agreed well with the experimental data. Covariate analysis showed that current body weight had a significant effect on the pharmacokinetics of cefoperazone. Monte Carlo simulation showed that for bacteria for which cefoperazone has an MIC of 0.5 mg/L, 78.1% of hypothetical children treated with ‘40 mg/kg/day, q8h, IV drip 3 h’ would reach the pharmacodynamic target. For bacteria for which cefoperazone has an MIC of 8 mg/L, 88.4% of hypothetical children treated with 80 mg/kg/day (continuous infusion) would reach the treatment goal. A 160 mg/kg/day (continuous infusion) regimen can cover bacteria for which cefoperazone has an MIC of 16 mg/L. Nevertheless, even if using the maximum reported dose of 160 mg/kg/day (continuous infusion), the ratio of hypothetical children reaching the treatment target was only 9.9% for bacteria for which cefoperazone has an MIC of 32 mg/L. Conclusions For cefoperazone, population pharmacokinetics were evaluated in children and an appropriate dosing regimen was developed based on developmental pharmacokinetics–pharmacodynamics. The dose indicated in the instructions (20–160 mg/kg/day) can basically cover the clinically common bacteria for which cefoperazone has an MIC of ≤16 mg/L. However, for bacteria for which the MIC is >16 mg/L, cefoperazone is not a preferred choice.

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 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 Isavuconazole Population Pharmacokinetic Analysis Using Nonparametric Estimation in Patients with Invasive Fungal Disease (Results from the VITAL Study)

2016 ◽  
Vol 60 (8) ◽  
pp. 4568-4576 ◽  
Author(s):  
Laura L. Kovanda ◽  
Amit V. Desai ◽  
Qiaoyang Lu ◽  
Robert W. Townsend ◽  
Shahzad Akhtar ◽  
...  
Keyword(s):  
Nonparametric Estimation ◽  
Invasive Fungal Disease ◽  
Fungal Disease ◽  
Water Soluble ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Open Label ◽  
Time Curve ◽  
Content Type

ABSTRACTIsavuconazonium sulfate (Cresemba; Astellas Pharma Inc.), a water-soluble prodrug of the triazole antifungal agent isavuconazole, is available for the treatment of invasive aspergillosis (IA) and invasive mucormycosis. A population pharmacokinetic (PPK) model was constructed using nonparametric estimation to compare the pharmacokinetic (PK) behaviors of isavuconazole in patients treated in the phase 3 VITAL open-label clinical trial, which evaluated the efficacy and safety of the drug for treatment of renally impaired IA patients and patients with invasive fungal disease (IFD) caused by emerging molds, yeasts, and dimorphic fungi. Covariates examined were body mass index (BMI), weight, race, impact of estimated glomerular filtration rate (eGFR) on clearance (CL), and impact of weight on volume. PK parameters were compared based on IFD type and other patient characteristics. Simulations were performed to describe the MICs covered by the clinical dosing regimen. Concentrations (n= 458) from 136 patients were used to construct a 2-compartment model (first-order absorption compartment and central compartment). Weight-related covariates affected clearance, but eGFR did not. PK parameters and intersubject variability of CL were similar across different IFD groups and populations. Target attainment analyses demonstrated that the clinical dosing regimen would be sufficient for total drug area under the concentration-time curve (AUC)/MIC targets ranging from 50.5 forAspergillusspp. (up to the CLSI MIC of 0.5 mg/liter) to 270 and 5,053 forCandida albicans(up to MICs of 0.125 and 0.004 mg/liter, respectively) and 312 for non-albicans Candidaspp. (up to a MIC of 0.125 mg/liter). The estimations forCandidaspp. were exploratory considering that no patients withCandidainfections were included in the current analyses. (The VITAL trial is registered at ClinicalTrials.gov under number NCT00634049.)

scholarly journals P61 Population pharmacokinetics of vancomycin in chinese ICU neonates: initial dosage recommendations

2019 ◽  
Vol 104 (6) ◽  
pp. e42.2-e42
Author(s):  
Z Li ◽  
Z Jiao
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Pharmacokinetic Model ◽  
Preterm Neonates ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Current Guideline ◽  
Mixed Effect ◽  
Pediatric Cancer Patients

The main goal of our study was to characterize the population pharmacokinetics of vancomycin in critically ill Chinese neonates to develop a pharmacokinetic model and investigate factors that have significant influences on the pharmacokinetics of vancomycin in this population.1 2 The study population consisted of 80neonates in the neonatal intensive care unit (ICU)from which 165 trough and peak concentrations of vancomycin were obtained.Nonlinear mixed effect modeling was used to develop a population pharmacokinetic model for vancomycin.4 The stability and predictive ability of the final model were evaluated based on diagnostic plots, normalized prediction distribution errorsandthe bootstrap method.Serum creatinine (Scr) and body weight were significant covariates on the clearance of vancomycin.5 6 The average clearance was 0.309L/h for a neonate with Scr of 23.3mmol/L and body weight of 2.9 kg. No obvious ethnic differences in the clearance of vancomycin were found relative to the earlier studies of Caucasian neonates. Moreover, the established model indicated that in patients with a greater renal clearance status, especially Scr < 15mmol/L,current guideline recommendationswould likely not achieve therapeuticarea under the concentration-time curve over24 h/minimum inhibitoryconcentration (AUC24h/MIC) ≥ 400.3 The exceptions to this areBritish National Formulary (2016–2017), Blue Book (2016) and Neofax (2017). Recommended dose regimensfor neonates with differentScrlevelsandpostmenstrual ageswere estimatedbased on Monte Carlo simulations andthe established model.These findings will be valuable for developing individualized dosage regimens in the neonatal ICU setting.ReferencesAbdel HO, Al OS, Nazer LH., Mubarak S, Le, J. Vancomycin pharmacokinetics and predicted dosage requirements in pediatric cancer patients. Journal of Oncology Pharmacy Practice 2015;22(3):448–453doi: 10.1177/1078155215591386Anderson, B. J., Allegaert, K., Jn, V. D. A., Cossey, V., &amp;Holford, N. H. ( 2007). Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance. British Journal of Clinical Pharmacolog;63(1):75–84. doi: 10.1111/j.1365-2125.2006.02725.xAllegaert K, Anderson BJ, Jn, VDA, Vanhaesebrouck, S., & De, Z. F. ( 2007). Renal drug clearance in preterm neonates: relation to prenatal growth. Therapeutic Drug Monitoring, 29(3), 284–291. doi: 10.1097/FTD.0b013e31806db3f5Byon, W., Smith, M. K., Chan, P., Tortorici, M. A., Riley, S., & Dai, H., et al. ( 2013). Establishing best practices and guidance in population modeling: an experience with an internal population pharmacokinetic analysis guidance. CptPharmacometrics & Systems Pharmacology,2(7), e51. doi: 10.1016/j.cmpb.2010.04.018Capparelli, E. V., Lane, F. R., Romanowski, G. L., Pharm, M. F., Murray, W., & Sousa, P., et al. ( 2001). The influences of renal function and maturation on vancomycin elimination in newborns and infants. Journal of Clinical Pharmacology, 41(9), 927–934.Centers for Disease Control and Prevention. ( 2009). WHO Child Growth Standards. http://www.who.int/childgrowth/en. [EB/OL] 2017-09-12Disclosure(s)Nothing to disclose

scholarly journals Population Pharmacokinetic Modelling and Simulation to Determine the Optimal Dose of Nanoparticulated Sorafenib to the Reference Sorafenib

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 629
Author(s):  
Ki Young Huh ◽  
Sejung Hwang ◽  
Sang Yeob Park ◽  
Hye Jung Lim ◽  
Miryung Jin ◽  
...  
Keyword(s):  
Compartmental Analysis ◽  
Optimal Dose ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Open Label ◽  
Post Dose ◽  
Multikinase Inhibitor ◽  
Final Model ◽  
Fasted State ◽  
Second Period

Sorafenib, an oral multikinase inhibitor, exhibits a highly variable absorption profile due to enterohepatic reabsorption and poor solubility. SYO-1644 improved the solubility of sorafenib by nanoparticulation technology leading to enhanced bioavailability. To evaluate the pharmacokinetically equivalent dose of SYO-1644 to the reference Nexavar® 200 mg, a randomized, open-label, replicated two-period study was conducted in healthy volunteers. A total of 32 subjects orally received a single dose of the following assigned treatment under a fasted state in the first period and repeated once more in the second period with a two-week washout: SYO-1644 100, 150 and 200 mg and Nexavar® 200 mg. Pharmacokinetic (PK) samples were collected up to 168 h post-dose. The PK profile was evaluated by both non-compartmental analysis and population PK method. With the final model, 2 × 2 crossover trial scenarios with Nexavar® 200 mg and each dose of SYO-1644 ranging from 100 to 150 mg were repeated 500 times by Monte Carlo simulation, and the proportion of bioequivalence achievement was assessed. Transit absorption compartments, followed by a one-compartment model with first-order elimination and enterohepatic reabsorption components were selected as the final model. The simulation results demonstrated that the SYO-1644 dose between 120 and 125 mg could yielded the highest proportion of bioequivalence.

scholarly journals Effect of Obesity on the Population Pharmacokinetics of Fluconazole in Critically Ill Patients

2016 ◽  
Vol 60 (11) ◽  
pp. 6550-6557 ◽  
Author(s):  
Abdulaziz S. Alobaid ◽  
Steven C. Wallis ◽  
Paul Jarrett ◽  
Therese Starr ◽  
Janine Stuart ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Maintenance Dose ◽  
Central Compartment ◽  
Pharmacokinetic Analysis ◽  
Morbidly Obese ◽  
Population Pharmacokinetic ◽  
Loading Dose ◽  
Intercompartmental Clearance

ABSTRACTOur objective was to describe the population pharmacokinetics of fluconazole in a cohort of critically ill nonobese, obese, and morbidly obese patients. Critically ill patients prescribed fluconazole were recruited into three body mass index (BMI) cohorts, nonobese (18.5 to 29.9 kg/m2), obese (30.0 to 39.9 kg/m2), and morbidly obese (≥40 kg/m2). Serial fluconazole concentrations were determined using a validated chromatographic method. Population pharmacokinetic analysis and Monte Carlo dosing simulations were undertaken with Pmetrics. Twenty-one critically ill patients (11 male) were enrolled, including obese (n= 6) and morbidly obese (n= 4) patients. The patients mean ± standard deviation (SD) age, weight, and BMI were 54 ± 15 years, 90 ± 24 kg, and 31 ± 9 kg/m2, respectively. A two-compartment linear model described the data adequately. The mean ± SD population pharmacokinetic parameter estimates were clearance (CL) of 0.95 ± 0.48 liter/h, volume of distribution of the central compartment (Vc) of 15.10 ± 11.78 liter, intercompartmental clearance from the central to peripheral compartment of 5.41 ± 2.28 liter/h, and intercompartmental clearance from the peripheral to central compartment of 2.92 ± 4.95 liter/h. A fluconazole dose of 200 mg daily was insufficient to achieve an area under the concentration-time curve for the free, unbound drug fraction/MIC ratio of 100 for pathogens with MICs of ≥2 mg/liter in patients with BMI of >30 kg/m2. A fluconazole loading dose of 12 mg/kg and maintenance dose of 6 mg/kg/day achieved pharmacodynamic targets for higher MICs. A weight-based loading dose of 12 mg/kg followed by a daily maintenance dose of 6 mg/kg, according to renal function, is required in critically ill patients for pathogens with a MIC of 2 mg/liter.

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