scholarly journals Population pharmacokinetics of cefotaxime in intensive care patients

2021 ◽  
Author(s):  
Maria Swartling ◽  
Anna-Karin Smekal ◽  
Mia Furebring ◽  
Miklos Lipcsey ◽  
Siv Jönsson ◽  
...  
Keyword(s):  
Intensive Care ◽  
Creatinine Clearance ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Icu Patients ◽  
Central Volume ◽  
The Impact

Abstract Purpose To characterise the pharmacokinetics and associated variability of cefotaxime in adult intensive care unit (ICU) patients and to assess the impact of patient covariates. Methods This work was based on data from cefotaxime-treated patients included in the ACCIS (Antibiotic Concentrations in Critical Ill ICU Patients in Sweden) study. Clinical data from 51 patients at seven different ICUs in Sweden, given cefotaxime (1000–3000 mg given 2–6 times daily), were collected from the first day of treatment for up to three consecutive days. In total, 263 cefotaxime samples were included in the population pharmacokinetic analysis. Results A two-compartment model with linear elimination, proportional residual error and inter-individual variability (IIV) on clearance and central volume of distribution best described the data. The typical individual was 64 years, with body weight at ICU admission of 92 kg and estimated creatinine clearance of 94 mL/min. The resulting typical value of clearance was 11.1 L/h, central volume of distribution 5.1 L, peripheral volume of distribution 18.2 L and inter-compartmental clearance 14.5 L/h. The estimated creatinine clearance proved to be a significant covariate on clearance (p < 0.001), reducing IIV from 68 to 49%. Conclusion A population pharmacokinetic model was developed to describe cefotaxime pharmacokinetics and associated variability in adult ICU patients. The estimated creatinine clearance partly explained the IIV in cefotaxime clearance. However, the remaining unexplained IIV is high and suggests a need for dose individualisation using therapeutic drug monitoring where the developed model, after evaluation of predictive performance, may provide support.

Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference

2021 ◽  
Author(s):  
Romain Garreau ◽  
Romain Bricca ◽  
Marie-Claude Gagnieu ◽  
Sandrine Roux ◽  
Anne Conrad ◽  
...  
Keyword(s):  
Joint Infection ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Individual Variability ◽  
Therapeutic Drug ◽  
Marginal Effect ◽  
Bone And Joint Infection ◽  
Two Compartment Model ◽  
Central Volume ◽  
Trough Concentrations

Abstract Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

scholarly journals Population Pharmacokinetic Analysis of Dexmedetomidine in Children using Real-World-Data Obtained from Electronic Health Records and Remnant Clinic Samples

2021 ◽  
Author(s):  
Nathan T James ◽  
Sara L Van Driest ◽  
Prince J Kannankeril ◽  
Leena Choi
Keyword(s):  
Real World ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Real World Data ◽  
World Data ◽  
Fixed Weight ◽  
Population Pk ◽  
Study Population ◽  
The Impact

Dexmedetomidine is commonly used as part of intraoperative anesthetic management and for sedation and pain control after surgery in children. Dexmedetomidine infusion dose is typically given on a fixed weight basis with titration to achieve sedation goals while avoiding potential toxicities. Pharmacokinetic (PK) studies are useful for accurate prediction of the individual dose required to achieve sedation and analgesia goals without toxicity, but lack of PK data is a challenge in precision dosing for pediatric populations. In this study, population PK models were developed using a nonlinear mixed-effects modeling approach and used to explore the relationship between PK profile and clinical, demographic, and genotype covariates. A simulation study was used to demonstrate the impact of important covariates on concentration using a fixed weight dosing scheme. Our final study population included data from 354 patients age 0 to 22 years (median age 16 months). In the final two-compartment model with fixed allometric weight scaling we found significant effects of both age and UGT2B10 genotype. The population PK parameter estimates (95% confidence interval) for a standard 70 kg weight were clearance 22.3 (18.3 - 27.3) L/hr, central compartment volume of distribution 133 (112 - 157) L, intercompartmental clearance 24.1 (19.4 - 29.9) L/hr, peripheral compartment volume of distribution 5230 (3310 - 8260) L. Our study provides support for the feasibility of using real-world data obtained from EHRs and remnant samples to perform population PK analysis for groups of patients where traditional PK studies are challenging to perform. Inclusion of UGT2B10 genotype in the model significantly improved the model fit, but the effects were not large enough to impact clinical dosing.

POPULATION PHARMACOKINETICS OF INTRAVENOUS ALBUTEROL IN CHILDREN WITH STATUS ASTHMATICUS

2015 ◽  
Vol 101 (1) ◽  
pp. e1.31-e1
Author(s):  
Nienke J Vet ◽  
Brenda CM de Winter ◽  
Saskia N de Wildt ◽  
Bart CH van der Nagel ◽  
Catherijne AJ Knibbe ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Status Asthmaticus ◽  
Clinical Symptoms ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Creatinine Concentration ◽  
Central Volume

ObjectivesTo develop a population pharmacokinetic model of R-albuterol and S-albuterol for children suffering from status asthmaticus following continuous intravenous administration.MethodsAt the pediatric ICU 19 children suffering from severe status asthmaticus were treated using continuous intravenous albuterol in doses based on clinical symptoms (range 0.1–10 µg/kg/min). During therapy 111 blood samples were collected and analysed for R- and S-albuterol using a validated LC/MS-MS method. A population pharmacokinetic analysis was conducted using non-linear mixed effects modelling (NONMEM 7.2). Data was logarithmically transformed. Model selection criteria were decrease in objective function, diagnostic plots and NPDE. The covariates (range) analysed were bodyweight (7.8–70 kg), age (0.8–15.3 years), creatinine concentration (17–70 µmol/L), alanine transaminase (5–29 IU/L), and urea (1.6–4.8 mmol/L).ResultsA two-compartment model with separated clearance for R- (16.3 L/h) and S-albuterol (8.8 L/h) best described the data. Separated values for central volume of distribution (12.9 L), peripheral volume of distribution (45.2 L) and intercompartmental clearance (20.0 L/h) did not improve the model. Between-subject variability was described for clearance of R-albuterol (42%), clearance of S-albuterol (37%) and central volume of distribution (280%). Weight is a significant covariate using a power function. The exponent of the powerfunction was fixed at 0.75 for clearance and intercompartmental and at 1 for central and peripheral volume of distribution. Estimation of the exponent resulted in similar values and did not improve the model. No other covariates were identified.ConclusionThe population pharmacokinetics of R- and S-albuterol are described. This model can be used to evaluate the correlation between albuterol pharmacokinetics and effect in a population pharmacokinetic-pharmacodynamic analysis.

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 Population Pharmacokinetics and Target Attainment of Cefepime in Critically Ill Patients and Guidance for Initial Dosing

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Mohammad H. Al-Shaer ◽  
Michael N. Neely ◽  
Jiajun Liu ◽  
Kartikeya Cherabuddi ◽  
Veena Venugopalan ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Elimination Rate ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Target Attainment ◽  
Icu Patients ◽  
The Mean ◽  
A Prospective Study

ABSTRACT Cefepime is commonly used in the intensive care unit (ICU) to treat bacterial infections. The time during which the free cefepime concentration is above the MIC (fT>MIC) should be optimized to increase the efficacy of the regimen. We aim to optimize the exposure of cefepime in ICU patients by using population pharmacokinetic (PK) modeling and simulations. Two data sets were included in this study. The first was a prospective study of pediatric patients who received cefepime at 50 mg/kg of body weight and had extensive PK sampling. The second study comprised retrospective data for adult ICU patients admitted to UF Health Shands Hospital who received cefepime and had their cefepime concentrations measured. The population PK model was developed, and simulations were performed, using Pmetrics. The target exposures were 100% fT>MIC and 100% fT>4×MIC. The studies included a total of 266 patients, and the mean ages were 3.9 years in the pediatric group and 55 years in adult group. More than half of the patients were males. The mean (standard deviation [SD]) creatinine clearance (CrCl) was 125 (93) ml/min. The mean (SD) daily dose for adults was 4.9 (1.6) g. Cefepime was well described by a two-compartment model with weight as a covariate on the volume of distribution and elimination rate constant (kel), and CrCl and age group as covariates on kel. At a MIC of 8 mg/liter, a cefepime loading dose of 4 g as an extended infusion followed by a 6-g continuous infusion was needed for good target attainment. In conclusion, prolonged or continuous infusions will be needed to achieve optimal cefepime exposure for ICU patients. Given the observed variability, therapeutic drug monitoring can help individualize therapy.

scholarly journals Covariate effects and population pharmacokinetic analysis of the anti-FGFR2b antibody bemarituzumab in patients from phase 1 to phase 2 trials

2021 ◽  
Author(s):  
Hong Xiang ◽  
Lucy Liu ◽  
Yuying Gao ◽  
Ago Ahene ◽  
Helen Collins
Keyword(s):  
Serum Concentration ◽  
Dose Adjustment ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
Phase 3 ◽  
The Impact ◽  
Significant Covariates

Abstract Purpose A population pharmacokinetic (PK) analysis of the anti-fibroblast growth factor receptor 2b antibody, bemarituzumab, was performed to evaluate the impact of covariates on the PK and assess whether dose adjustment is necessary for a future phase 3 trial. Methods Serum concentration data were obtained from three clinical trials, with 1552 bemarituzumab serum samples from 173 patients, and were analyzed using nonlinear mixed-effects modeling. Results A two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment best described the bemarituzumab serum concentration data. The final model estimated a typical linear clearance (CL) of 0.311 L/day, volume of distribution in the central compartment (Vc) of 3.58 L, distribution clearance (Q) of 0.952 L/day, volume of distribution in the peripheral compartment (Vp) of 2.71 L, maximum drug elimination by nonlinear clearance (Vmax) of 2.80 μg/day, and Michaelis–Menten constant (Km) of 4.45 μg/mL. Baseline body weight, baseline albumin, gender, and chemotherapy were identified as statistically significant covariates on the PK of bemarituzumab. Given the low interindividual variability of bemarituzumab key PK parameters (CL and Vc) and the small or modest effect of all statistically significant covariates on bemarituzumab exposure at steady-state, no covariate is expected to have clinically meaningful effects on bemarituzumab exposure. Conclusion No covariate had a clinically meaningful impact on bemarituzumab exposure. These results indicate that dose adjustment of bemarituzumab is not necessary, based on the aforementioned covariates, for a future phase 3 trial in gastric and gastroesophageal junction adenocarcinoma population with FGFR2b overexpression in combination with mFOLFOX6.

Procainamide pharmacokinetics during extracorporeal membrane oxygenation

Perfusion ◽  
2021 ◽  
pp. 026765912110506
Author(s):  
Nicholas J Vollmer ◽  
Erica D Wittwer ◽  
Andrew N Rosenbaum ◽  
Patrick M Wieruszewski
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Elevated Serum ◽  
Stable Condition ◽  
Pharmacokinetic Profile ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Therapeutic Drug ◽  
Slow Acetylator ◽  
Membrane Oxygenation ◽  
Serum And Urine

Procainamide is a useful agent for management of ventricular arrhythmia, however its disposition and appropriate dosing during extracorporeal membrane oxygenation (ECMO) is unknown. We report experience with continuous procainamide infusion in a critically ill adult requiring venoarterial ECMO for incessant ventricular tachycardia. Pharmacokinetic analysis of procainamide and its metabolite, N-acetylprocainamide (NAPA), was performed using serum and urine specimens. Kidney function was preserved, and sequencing of the N-acetyltransferase 2 gene revealed the patient was a phenotypic slow acetylator. Procainamide volume of distribution and half-life were calculated and found to be similar to healthy individuals. However, despite elevated serum procainamide concentrations, NAPA concentrations remained far lower in the serum and urine. The magnitude of procainamide and NAPA discordance suggested alternative contributors to the deranged pharmacokinetic profile, and we hypothesized NAPA sequestration by the ECMO circuit. Ultimately, the patient received orthotopic cardiac transplantation and was discharged home in stable condition. Procainamide should be used cautiously during ECMO, with close therapeutic drug monitoring of serum procainamide and NAPA concentrations. The achievement of therapeutic NAPA concentrations while maintaining safe serum procainamide concentrations during ECMO support may be challenging.

scholarly journals Influence of Mechanical Ventilation on the Pharmacokinetics of Vancomycin Administered by Continuous Infusion in Critically Ill Patients

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Susanna Edith Medellín-Garibay ◽  
Silvia Romano-Moreno ◽  
Pilar Tejedor-Prado ◽  
Noelia Rubio-Álvaro ◽  
Aida Rueda-Naharro ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Creatinine Clearance ◽  
Continuous Infusion ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Stochastic Simulations ◽  
Population Pharmacokinetic

ABSTRACT Pathophysiological changes involved in drug disposition in critically ill patients should be considered in order to optimize the dosing of vancomycin administered by continuous infusion, and certain strategies must be applied to reach therapeutic targets on the first day of treatment. The aim of this study was to develop a population pharmacokinetic model of vancomycin to determine clinical covariates, including mechanical ventilation, that influence the wide variability of this antimicrobial. Plasma vancomycin concentrations from 54 critically ill patients were analyzed simultaneously by a population pharmacokinetic approach. A nomogram for dosing recommendations was developed and was internally evaluated through stochastic simulations. The plasma vancomycin concentration-versus-time data were best described by a one-compartment open model with exponential interindividual variability associated with vancomycin clearance and the volume of distribution. Residual error followed a homoscedastic trend. Creatinine clearance and body weight significantly dropped the objective function value, showing their influence on vancomycin clearance and the volume of distribution, respectively. Characterization based on the presence of mechanical ventilation demonstrated a 20% decrease in vancomycin clearance. External validation (n = 18) was performed to evaluate the predictive ability of the model; median bias and precision values were 0.7 mg/liter (95% confidence interval [CI], −0.4, 1.7) and 5.9 mg/liter (95% CI, 5.4, 6.4), respectively. A population pharmacokinetic model was developed for the administration of vancomycin by continuous infusion to critically ill patients, demonstrating the influence of creatinine clearance and mechanical ventilation on vancomycin clearance, as well as the implications for targeting dosing rates to reach the therapeutic range (20 to 30 mg/liter).

Evaluation of Intravenous Phenobarbital Pharmacokinetics in Critically Ill Patients With Brain Injury

2022 ◽  
Author(s):  
Seyedeh Sana Khezrnia ◽  
Bita Shahrami ◽  
Mohammad Reza Rouini ◽  
Atabak Najafi ◽  
Hamid Reza Sharifnia ◽  
...  
Keyword(s):  
Brain Injury ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Normal Population ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Therapeutic Drug ◽  
Uv Detector ◽  
Therapeutic Goals ◽  
The Impact

Phenobarbital is still one of the drugs of choice in managing patients with brain injury in the intensive care unit (ICU). However, the impact of acute physiological changes on phenobarbital pharmacokinetic parameters is not well studied. This study aimed to evaluate the pharmacokinetic parameters of parenteral phenobarbital in critically ill patients with brain injury. Patients with severe traumatic or non-traumatic brain injury at high risk of seizure were included and followed for seven days. All patients initially received phenobarbital as a loading dose of 15 mg/kg over 30-minutes infusion, followed by 2 mg/kg/day divided into three doses. Blood samples were obtained on the first and fourth day of study at 1, 2, 5, 8, and 10 hours after the end of the infusion. Serum concentrations of phenobarbital were measured by high-pressure liquid chromatography (HPLC) with an ultraviolet (UV) detector. Pharmacokinetic parameters, including the volume of distribution (Vd), half-life (t1/2), and the drug clearance (CL), were provided by MonolixSuite 2019R1 software using stochastic approximation expectation-maximization (SAEM) algorithm and compared with previously reported parameters in healthy volunteers. Data from seventeen patients were analyzed. The mean value±standard deviation of pharmacokinetic parameters was calculated as follows: Vd: 0.81±0.15 L/kg; t1/2: 6.16±2.66 days; CL: 4.23±1.51 ml/kg/h. CL and Vd were significantly lower and higher than the normal population with the value of 5.6 ml/kg/h (P=0.002) and 0.7 L/kg (P=0.01), respectively. Pharmacokinetic behavior of phenobarbital may change significantly in critically ill brain-injured patients. This study affirms the value of early phenobarbital therapeutic drug monitoring (TDM) to achieve therapeutic goals.

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