scholarly journals Population Pharmacokinetics and Pharmacodynamic Implementation of Meropenem in Critically Ill Pediatric Patients

2020 ◽  
Author(s):  
Jumpei Saito ◽  
Kensuke Shoji ◽  
Yusuke Oho ◽  
Hiroki Kato ◽  
Shotaro Matsumoto ◽  
...  
Keyword(s):  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Intensive Care ◽  
Volume Of Distribution ◽  
Dosing Regimen ◽  
Final Model ◽  
The Mean ◽  
Higher Doses ◽  
Volumes Of Distribution ◽  
Significant Covariates

This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03–14.6) years old and 8.9 (2.7–40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), of which three received extracorporeal membrane oxygenation. Renal function, systemic inflammatory response syndrome (SIRS) score, and the use of CRRT for central volumes of distribution (Vc) were identified as significant covariates. The mean clearance (CL), Vc, and peripheral volume of distribution (Vp) were 0.45 l/kg/h, 0.49 l/kg, and 0.34 l/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and Vc increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of 100% free time above the minimum inhibitory concentration, and higher doses (40–80 mg/kg/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary.

scholarly journals Population Pharmacokinetics of Rituximab in Pediatric Patients With Frequent-Relapsing or Steroid-Dependent Nephrotic Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Yewei Chen ◽  
Qian Shen ◽  
Min Dong ◽  
Ye Xiong ◽  
Hong Xu ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Pediatric Patients ◽  
Volume Of Distribution ◽  
Therapeutic Effects ◽  
Dosing Regimen ◽  
Open Label ◽  
Steroid Dependent ◽  
Central Volume ◽  
Higher Doses ◽  
Steroid Dependent Nephrotic Syndrome

Objectives: Rituximab is frequently used off-label for the treatment of frequent-relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS), but the relapse rate remained high and the dosing regimen varied widely. The objective of this study was to characterize rituximab pharmacokinetics (PK) in pediatric patients with FRNS/SDNS, and to investigate the differences in rituximab PK between patients with FRNS/SDNS and other disease populations.Methods: Fourteen pediatric patients received rituximab for FRNS/SDNS treatment were enrolled in a prospective, open-label, single-center PK study. A population PK model of rituximab was developed and validated, and PK parameters were derived for quantitative evaluation.Results: A two-compartment PK model best described the data. Body surface area was the most significant covariate for both central clearance (CL) and apparent central volume of distribution (V1). Patients with FRNS/SDNS exhibited a clinically relevant increase in rituximab CL compared to patient population with non-Hodgkin’s lymphoma (NHL).Conclusion: This pilot study indicated that higher doses or more frequent regimens of rituximab may be required for optimal therapeutic effects in patients with FRNS/SDNS. Further clinical studies with more patients are warranted to confirm this result.

scholarly journals Influence of maturation and growth on cefetamet pivoxil pharmacokinetics: rational dosing for infants.

1996 ◽  
Vol 40 (3) ◽  
pp. 567-574 ◽  
Author(s):  
W L Hayton ◽  
J Kneer ◽  
R de Groot ◽  
K Stoeckel
Keyword(s):  
Body Weight ◽  
Half Life ◽  
Pediatric Patients ◽  
Volume Of Distribution ◽  
Systemic Clearance ◽  
Older Children ◽  
Dosing Regimen ◽  
Urinary Recovery ◽  
The Mean ◽  
Plasma Half Life

The pharmacokinetics of intravenous (i.v.) cefetamet and the bioavailability of oral cefetamet pivoxil in infants aged 3.5 to 17.3 months who were hospitalized for urological surgery were characterized. The absorption of cefetamet pivoxil administered in a syrup formulation was 38 +/- 19% (n = 5) for infants, which was comparable to values observed for children and adults. The plasma half-life of i.v. cefetamet was 3.03 +/- 0.96 h (mean +/- standard deviation; n = 20) in the infants. This was not different from the value observed for normal adult subjects but was longer than that reported for children aged 3 to 12 years. Urinary recovery of cefetamet after i.v. administration to infants was 63.4 +/- 17.7% (n = 16), which was less than the 80% recovery found in older children and adults. The steady-state volume of distribution was 399 +/- 116 ml/kg of body weight. It was comparable in size and showed the same dependence on body weight as it did in children and adults. The mean systemic clearance per kilogram of body weight in the infants was lower than that in children and adults, apparently because of immaturity of clearance processes. A model that accounted for maturation and growth with increasing age was developed for the clearance. On the basis of this model, the clearance capacity increased from birth to 5 years by a factor of 4.5 because of maturation. Maturation progressed exponentially, with a half-life of 14 months. This model was used to develop dosing regimen guidelines for pediatric patients aged 3.5 months and older.

scholarly journals Cefepime Pharmacokinetics in Critically Ill Pediatric Patients Receiving Continuous Renal Replacement Therapy

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Gideon Stitt ◽  
Jennifer Morris ◽  
Lindsay Schmees ◽  
Joseph Angelo ◽  
Ayse Akcan Arikan
Keyword(s):  
Intensive Care Unit ◽  
Body Weight ◽  
Intensive Care ◽  
Retrospective Study ◽  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Intensive Care ◽  
Free Drug ◽  
Therapeutic Drug ◽  
Free Drug Concentration

ABSTRACT This retrospective study included pediatric intensive care unit patients receiving continuous veno-venous hemodiafiltration (CVVHDF) being treated with cefepime. The free drug concentration above one time the MIC (fT>1×MIC) and four times a presumed MIC (fT>4×MIC) of 8 μg/ml were calculated. Four patients received doses ranging from 48 to 64 mg/kg of body weight every 6 to 12 h. Three patients achieved 100% fT>1×MIC, with the fourth patient achieving 98% fT>1×MIC. Therapeutic drug monitoring should be considered for critically ill patients receiving cefepime on CVVHDF.

scholarly journals 1573. Population Pharmacokinetic Analyses for Cefepime in Adult and Pediatric Patients

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S574-S575
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade B Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Rate Constant ◽  
Pediatric Patients ◽  
Validation Cohort ◽  
External Validation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Information Criteria ◽  
Population Pharmacokinetic ◽  
Final Model ◽  
Two Compartment Model

Abstract Background Cefepime (CEF) is commonly used for adult and pediatric infections. Several studies have examined CEF’s pharmacokinetics (PK) in various populations; however, a unifying PK model for adult and pediatric subjects does not yet exist. We developed a combined population model for adult and pediatric patients and validated the model. Methods The initial model includes adult and pediatric patients with a rich cefepime sampling design. All adults received 2 g CEF while pediatric subjects received a mean of 49 (SD 5) mg/kg. One- and two-compartment models were considered as base models and were fit using a non-parametric adaptive grid algorithm within the Pmetrics package 1.5.2 (Los Angeles, CA) for R 3.5.1. Compartmental model selection was based on Akaike information criteria (AIC). Covariate relationships with PK parameters were visually inspected and mathematically assessed. Predictive performance was evaluated using bias and imprecision of the population and individual prediction models. External validation was conducted using a separate adult cohort. Results A total of 45 subjects (n = 9 adults; n = 36 pediatrics) were included in the initial PK model build and 12 subjects in the external validation cohort. Overall, the data were best described using a two-compartment model with volume of distribution (V) normalized to total body weight (TBW/70 kg) and an allometric scaled elimination rate constant (Ke) for pediatric subjects (AIC = 4,138.36). Final model observed vs. predicted plots demonstrated good fit (population R2 = 0.87, individual R2 = 0.97, Figure 1a and b). For the final model, the population median parameter values (95% credibility interval) were V0 (total volume of distribution), 11.7 L (10.2–14.6); Ke for adult, 0.66 hour−1 (0.38–0.78), Ke for pediatrics, 0.82 hour−1 (0.64–0.85), KCP (rate constant from central to peripheral compartment), 1.4 hour−1 (1.3–1.8), KPC (rate constant from peripheral to central compartment), 1.6 hour−1 (1.2–1.8). The validation cohort has 12 subjects, and the final model fit the data well (individual R2 = 0.75). Conclusion In this diverse group of adult and pediatrics, a two-compartment model described CEF PK well and was externally validated with a unique cohort. This model can serve as a population prior for real-time PK software algorithms. Disclosures All authors: No reported disclosures.

scholarly journals Population Pharmacokinetics of Pyrazinamide in Patients with Tuberculosis

2017 ◽  
Vol 61 (6) ◽  
Author(s):  
Abdullah Alsultan ◽  
Rada Savic ◽  
Kelly E. Dooley ◽  
Marc Weiner ◽  
William Whitworth ◽  
...  
Keyword(s):  
Body Weight ◽  
Therapeutic Target ◽  
Volume Of Distribution ◽  
Current Treatment ◽  
Population Pharmacokinetic ◽  
Maximum Plasma ◽  
Target Attainment ◽  
Time Curve ◽  
The Mean ◽  
Higher Doses

ABSTRACT The current treatment used for tuberculosis (TB) is lengthy and needs to be shortened and improved. Pyrazinamide (PZA) has potent sterilizing activity and has the potential to shorten the TB treatment duration, if treatment is optimized. The goals of this study were (i) to develop a population pharmacokinetic (PK) model for PZA among patients enrolled in PK substudies of Tuberculosis Trial Consortium (TBTC) trials 27 and 28 and (ii) to determine covariates that affect PZA PK. (iii) We also performed simulations and target attainment analysis using the proposed targets of a maximum plasma concentration (C max) of >35 μg/ml or an area under the concentration-versus-time curve (AUC) of >363 μg · h/ml to see if higher weight-based dosing could improve PZA efficacy. Seventy-two patients participated in the substudies. The mean (standard deviation [SD]) C max was 30.8 (7.4) μg/ml, and the mean (SD) AUC from time zero to 24 h (AUC0–24) was 307 (83) μg · h/ml. A one-compartment open model best described PZA PK. Only body weight was a significant covariate for PZA clearance. Women had a lower volume of distribution (V/F) than men, and both clearance (CL/F) and V/F increased with body weight. Our simulations show that higher doses of PZA (>50 mg/kg of body weight) are needed to achieve the therapeutic target of an AUC/MIC of >11.3 in >80% of patients, while doses of >80 mg/kg are needed for target attainment in 90% of patients, given specific assumptions about MIC determinations. For the therapeutic targets of a C max of >35 μg/ml and/or an AUC of >363 μg · h/ml, doses in the range of 30 to 40 mg/kg are needed to achieve the therapeutic target in >90% of the patients. Further clinical trials are needed to evaluate the safety and efficacy of higher doses of PZA.

scholarly journals Phase I Pharmacokinetic and Pharmacodynamic Study of Temozolomide in Pediatric Patients With Refractory or Recurrent Leukemia: A Children's Oncology Group Study

2007 ◽  
Vol 25 (31) ◽  
pp. 4922-4928 ◽  
Author(s):  
Terzah M. Horton ◽  
Patrick A. Thompson ◽  
Stacey L. Berg ◽  
Peter C. Adamson ◽  
Ashish M. Ingle ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Dna Methyltransferase ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Tissue Bank ◽  
Volume Of Distribution ◽  
Methylguanine Dna Methyltransferase ◽  
Pediatric All ◽  
The Mean

Purpose To determine the tolerability, pharmacokinetics, and mechanisms of temozolomide resistance in children with relapsed or refractory leukemia. Patients and Methods Cohorts of three to six patients received 200 or 260 mg/m2/d of temozolomide by mouth daily for 5 days every 28 days. Toxicities, clinical response, and pharmacokinetics were evaluated. Pretreatment leukemia cell O6-methylguanine–DNA methyltransferase (MGMT) activity, tumor and plasma MGMT promoter methylation, and microsatellite instability (MSI) were examined in 14 of 16 study patients and in tissue bank samples from children with acute leukemia not treated with temozolomide (MGMT, n = 67; MSI, n = 65). Results Sixteen patients (nine female, seven male; acute lymphoblastic leukemia [ALL], n = 8; acute myeloid leukemia [AML], n = 8), median age 11 years (range, 1 to 19 years), received either 200 mg/m2/d (nine enrolled, three assessable for toxicity) or 260 mg/m2/d (seven enrolled, three assessable for toxicity) of temozolomide. Temozolomide was well tolerated and no dose-limiting toxicities occurred. The mean clearance of temozolomide was 107 mL/min/m2, with a volume of distribution of 20 L/m2 and half-life of 109 minutes. MGMT activity in leukemia cells was quite variable and was highest in patients with relapsed ALL. Only one patient had MSI. Two patients had a partial response. Both of these patients had no detectable MGMT activity; both also had methylated MGMT promoters and were MSI stable. Conclusion Temozolomide was well tolerated at doses as high as 260 mg/m2/d for 5 days in children with relapsed or refractory leukemia. Increased MGMT activity may account for the temozolomide resistance in children with relapsed leukemia. Leukemia cell MGMT activity was higher in pediatric ALL than AML (P < .0001).

scholarly journals Antithrombin III Doses Rounded to Available Vial Sizes in Critically Ill Pediatric Patients

2017 ◽  
Vol 22 (1) ◽  
pp. 15-21
Author(s):  
Winifred M. Stockton ◽  
Eimeira Padilla-Tolentino ◽  
Carolyn E. Ragsdale
Keyword(s):  
Critically Ill ◽  
Low Molecular Weight Heparin ◽  
Pediatric Patients ◽  
Antithrombin Iii ◽  
Cost Savings ◽  
Pediatric Intensive Care ◽  
Acute Illness ◽  
Low Molecular Weight ◽  
Dose Administration ◽  
At Iii

OBJECTIVES Children have decreased levels of antithrombin III (AT III) compared to adults. These levels may be further decreased during acute illness. Administration of exogenous AT III can increase anticoagulant efficacy. The objective of this study was to evaluate AT III doses rounded to available vial sizes compared to partial vial doses in critically ill pediatric patients, including patients receiving extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT). METHOD This retrospective review evaluated pediatric patients 0–18 years of age admitted to a 24-bed medical/surgical pediatric intensive care unit between June 1, 2012, and December 31, 2014, who received plasma-derived AT III. Patients received unfractionated heparin, low-molecular-weight heparin, or no anticoagulation. This review included patients who received ECMO and CRRT. RESULTS Eighty doses of AT III were administered to 24 patients (38 full vial size doses and 42 partial vial size doses). The AT III level following dose administration was ≥80% for 26 full vial doses (70%) and 16 partial vial doses (41%; p = 0.010). For patients who received multiple doses of AT III, the median time between doses was 45 hours following full vial doses, and 23 hours following partial vial doses (p = 0.011). Seven patients (29%) had documentation of new or increased bleeding. The median waste prevented from rounding doses to full vial sizes was 363 units. CONCLUSIONS After receiving AT III doses rounded to full vial sizes, patients were more likely to have a therapeutic AT III level and a longer interval between administrations. Rounding AT III doses to full vial sizes reduces waste and can result in cost savings.

scholarly journals Full outline of unresponsiveness score as a predictor of outcomes in critically ill pediatric patients

2020 ◽  
Vol 60 (2) ◽  
pp. 77-82
Author(s):  
Novita Purnamasari Assa ◽  
Dyah Kanya Wati ◽  
Ida Bagus Subanada ◽  
Soetjiningsih Soetjiningsih ◽  
Made Kardana ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Critically Ill ◽  
Pediatric Patients ◽  
Pediatric Intensive Care ◽  
Bivariate Analysis ◽  
Chi Square ◽  
Risk Of Death ◽  
Good Ability ◽  
Chi Square Test ◽  
Four Score

Background Mortality predictions are very important for improving service quality in the pediatric intensive care unit (PICU). The full outline of unresponsiveness (FOUR) is a new coma scale and is considered capable of predicting mortality and outcome. Objective To assess the ability of FOUR scores to predict outcomes of critically ill patients in the PICU. Methods This prospective cohort study included children aged 1 months - 18 years who were admitted to the PICU. Subjects were assessed by FOUR, grouped into score < 9 or score >9, and followed until outcomes were obtained. Bivariate analysis to assess the risk of death was made by cross-tabulation and the strength of the association in the form of risk ratio by Chi-square test. Multivariate analysis was done by logistic regression test. Results Of 94 subjects, 47 had FOUR scores ≤9 and 47 subjects had FOUR >9. Bivariate analysis revealed that PICU patients with FOUR score ≤9 had a higher risk of death than those with FOUR score >9 (RR 12.5; 95%CI 3.1 to 49.8; P<0.0001). Multivariate analysis revealed that FOUR score, length of stay ≤7 days, and non-surgical disease significantly increased the risk of mortality in PICU patients (by 42.8 times, 8.9 times, and 5.9 times, respectively). Conclusion The FOUR scores have good ability to predict the outcomes of critically ill pediatric patients. A FOUR score ≤9 at the beginning of treatment is significantly associated with the outcome of mortality during treatment in the PICU.

scholarly journals Association between early fluid overload and mortality in critically-ill mechanically ventilated children: a single-center retrospective cohort study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xiangmei Kong ◽  
Yueniu Zhu ◽  
Xiaodong Zhu
Keyword(s):  
Hospital Mortality ◽  
Critically Ill ◽  
Fluid Overload ◽  
Pediatric Intensive Care ◽  
Multiple Organ ◽  
Mechanically Ventilated ◽  
The Mean ◽  
Severity Of The Disease ◽  
Early Fluid ◽  
The Relationship

Abstract Background Positive fluid overload (FO) may cause adverse effect. This study retrospectively analyzed the relationship between early FO and in-hospital mortality in children with mechanical ventilation (MV) in pediatric intensive care unit (PICU). Methods This study retrospectively enrolled 309 children (ages 28 days to 16 years) receiving invasive MV admitted to the PICU of Xinhua Hospital from March 2014 to March 2019. Children receiving MV for less than 48 h were excluded. The FO in the first 3 days of MV was considered to the early FO. Patients were divided into groups according to early FO and survival to evaluate the associations of early FO, percentage FO(%FO) > 10%, and %FO > 20% with in-hospital mortality. Results A total of 309 patients were included. The mean early FO was 8.83 ± 8.81%, and the mortality in hospital was 26.2% (81/309). There were no significant differences in mortality among different FO groups (P = 0.053) or in early FO between survivors and non-survivors (P = 0.992). Regression analysis demonstrated that use of more vasoactive drugs, the presence of multiple organ dysfunction syndrome, longer duration of MV, and a non-operative reason for PICU admission were related to increased mortality (P < 0.05). Although early FO and %FO > 10% were not associated with in-hospital mortality (β = 0.030, P = 0.090, 95% CI = 0.995–1.067; β = 0.479, P = 0.153, 95% CI = 0.837–3.117), %FO > 20% was positively correlated with mortality (β = 1.057, OR = 2.878, P = 0.029, 95% CI = 1.116–7.418). Conclusions The correlation between early FO and mortality was affected by interventions and the severity of the disease, but %FO > 20% was an independent risk factor for in-hospital mortality in critically ill MV-treated children.

scholarly journals Piperacillin/Tazobactam and Antibiotic-Associated Acute Kidney Injury in Critically Ill Children

2019 ◽  
Vol 30 (11) ◽  
pp. 2243-2251 ◽  
Author(s):  
Emily L. Joyce ◽  
Sandra L. Kane-Gill ◽  
Priyanka Priyanka ◽  
Dana Y. Fuhrman ◽  
John A. Kellum
Keyword(s):  
Intensive Care ◽  
Critically Ill ◽  
Primary Outcome ◽  
Pediatric Patients ◽  
Kidney Injury ◽  
Pediatric Intensive Care ◽  
Critically Ill Children ◽  
Lengths Of Stay ◽  
Medication Exposure ◽  
Secondary Outcomes

BackgroundThere continues to be uncertainty about whether piperacillin/tazobactam (TZP) increases the risk of AKI in critically ill pediatric patients. We sought to compare rates of AKI among critically ill children treated with TZP or cefepime, an alternative frequently used in intensive care units, with and without vancomycin.MethodsWe conducted a retrospective cohort study assessing the risk of AKI in pediatric intensive care unit patients after exposure to vancomycin, TZP, and cefepime, alone or in combination, within 48 hours of admission. The primary outcome was development of stage 2 or 3 AKI or an increase in AKI stage from 2 to 3 within the 6 days after the 48-hour exposure window. Secondary outcomes included lengths of stay, need for RRT, and mortality.ResultsOf 5686 patients included, 494 (8.7%) developed stage 2 or 3 AKI. The adjusted odds of developing AKI after medication exposure were 1.56 for TZP (95% confidence interval [95% CI], 1.23 to 1.99), 1.13 for cefepime (95% CI, 0.79 to 1.64), and 0.86 for vancomycin (95% CI, 0.69 to 1.07). The adjusted odds of developing AKI for vancomycin plus TZP versus vancomycin plus cefepime was 1.38 (95% CI, 0.85 to 2.24).ConclusionsObservational data in critically ill children show that TZP use is associated with increased odds of AKI. A weaker, nonsignificant association between vancomycin plus TZP and AKI compared with vancomycin plus cefepime, creates some uncertainty about the nature of the association between TZP and AKI. However, cefepime is an alternative not associated with AKI.

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