scholarly journals A Practical Tranexamic Acid Dosing Scheme Based on Population Pharmacokinetics in Children Undergoing Cardiac Surgery

2013 ◽  
Vol 118 (4) ◽  
pp. 853-862 ◽  
Author(s):  
Stanislas Grassin-Delyle ◽  
Roland Couturier ◽  
Emuri Abe ◽  
Jean Claude Alvarez ◽  
Philippe Devillier ◽  
...  
Keyword(s):  
Body Weight ◽  
Cardiac Surgery ◽  
Tranexamic Acid ◽  
Population Pharmacokinetics ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Pediatric Cardiac Surgery ◽  
Pharmacokinetic Parameters ◽  
Risk For Bleeding ◽  
First Time

Abstract Background: Pediatric cardiac surgery patients are at high risk for bleeding, and the antifibrinolytic drug tranexamic acid (TA) is often used to reduce blood loss. However, dosing schemes remain empirical as a consequence of the absence of pharmacokinetic study in this population. The authors’ objectives were thus to investigate the population pharmacokinetics of TA in pediatric cardiac surgery patients during cardiopulmonary bypass (CPB). Methods: Twenty-one patients were randomized to receive TA either continuously (10 mg/kg followed by an infusion of 1 mg·kg−1·h−1 throughout the operation, and 10 mg/kg into the CPB) or discontinuously (10 mg/kg, then 10 mg/kg into the CPB and 10 mg·kg−1·h−1 at the end of CPB). Serum concentrations were measured at eight time points with chromatography–mass spectrometry and the data were modeled using Monolix (Lixoft, Orsay, France). Results: Tranexamic acid pharmacokinetics was ascribed to a two-compartment open model. The main covariate effects were body weight and CPB. Representative pharmacokinetic parameters adjusted to a 70-kg body weight were as follows: systemic clearance, 2.45 l/h; volume of distribution in the central compartment, 14.1 l; intercompartmental clearance, 5.74 l/h; and peripheral volume, 32.8 l. In accordance with this model, the authors proposed a weight-adjusted dosing scheme to maintain effective TA concentrations in children during surgery, consisting of one loading dose followed by a continuous infusion. Conclusions: The authors report for the first time the pharmacokinetics of TA in children undergoing cardiac surgery with CPB, and propose a dosing scheme for optimized TA administration in those children.

Population Pharmacokinetics of Enoxaparin in Children at Risk for Symptomatic Thromboembolism.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1071-1071
Author(s):  
Mirjam Nadine Trame ◽  
Lesley Mitchell ◽  
Christoph Male ◽  
Jeffrey S. Barrett ◽  
Georg Hempel ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Maintenance Dose ◽  
Factor Xa ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Safety And Efficacy ◽  
Off Label ◽  
Final Population

Abstract Abstract 1071 Poster Board I-93 Introduction: Enoxaparin, a low-molecular-weight-heparin (LMWH), is used off-label in children to prevent symptomatic thromboembolism when acute anticoagulation or secondary prevention is required due to venous thrombosis or stroke. This investigation was conducted because of concerns of altered pharmacokinetics and a lack of safety and efficacy data when used in children. Patients and Methods: Data of 126 children and adolescents with a median age of 5.9 years receiving enoxaparin either as a once or twice daily dosing regimen were analyzed. Children < 12 months of age received a starting dose of 1.5 mg/kg followed by a maintenance dose of 1.3 mg/kg. Children > 12 months of age were started on 1 mg/kg followed by a maintenance dose of 1 mg/kg. Blood samples were drawn after patients reached steady-state on their maintenance dose at baseline prior to the next dose, and at 2, 4, 8 and 12 hours after administration. The median enoxaparin concentration in our population resulted in a median anti-factor Xa activity of 0.4 U/ml (range 0 – 1 U/ml anti-factor Xa). By means of population pharmacokinetics using nonlinear mixed-effects modelling (NONMEM) plasma concentration-time data were analyzed. Several covariates such as age, body weight and body surface area were tested on their effects on the pharmacokinetic parameters. Results: Using a two-compartment model the enoxaparin kinetics were described sufficiently. By using body weight and age as covariates for clearance (CL) and central volume of distribution (V1) the best results were obtained. The final population estimates of enoxaparin resulted to be: CL 7.11 ml h-1 kg-1 ± 14.3%, V1 7.31 ml kg-1 ± 33.5%, intercompartimental clearance (Q) 194 ml h-1 ± 24.7%, peripheral volume of distribution (V2) 45.1 l ± 52.5% and absorption rate (ka) 0.0799 h-1 ± 21.7% (estimates ± standard errors). Interindividual variability (IIV) was found to be 75.6% for CL and 78.4% for Q, respectively. Figure 1 shows the predicted activity time-course versus the measured activities for a representative patient. The model is capable of describing all aging and dosing groups of our childhood population (neonates, infants to adolescents). Conclusion: The high IIV in CL and Q in our population underlines the need for monitoring the activity and individualizing the dose. Further population pharmacokinetic/-dynamic investigations should be conducted to predict target enoxaparin levels or other new antithrombotic drugs for more safety and efficacy during antithrombotic therapy when used in children. Disclosures: Off Label Use: Enoxaparin (LMWH) is used off-label in children to prevent symptomatic thromboembolism..

scholarly journals Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

2001 ◽  
Vol 45 (6) ◽  
pp. 1803-1809 ◽  
Author(s):  
Sanjeev Krishna ◽  
Nelamangala V. Nagaraja ◽  
Tim Planche ◽  
Tsiri Agbenyega ◽  
George Bedo-Addo ◽  
...  
Keyword(s):  
Body Weight ◽  
Severe Malaria ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Intravenous Route ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Loading Dose

ABSTRACT We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n = 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] = 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V 1] = 0.65 liter/kg; volume of distribution at steady state = 1.41 liter/kg; half-life at β phase = 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weight-normalized CL and V 1. Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.

Population Pharmacokinetics of Cefoxitin Administered for Pediatric Cardiac Surgery Prophylaxis

2020 ◽  
Vol 39 (7) ◽  
pp. 609-614
Author(s):  
Zaccaria Ricci ◽  
Simona Benegni ◽  
Jeffrey J. Cies ◽  
Eleonora Marinari ◽  
Roberta Haiberger ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Population Pharmacokinetics ◽  
Pediatric Cardiac Surgery

Vancomycin volume of distribution estimation in adults with class III obesity

2019 ◽  
Author(s):  
Ryan D Dunn ◽  
Ryan L Crass ◽  
Joseph Hong ◽  
Manjunath P Pai ◽  
Lynne C Krop
Keyword(s):  
Body Weight ◽  
Total Body Weight ◽  
Volume Of Distribution ◽  
Patient Specific ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Parameter Estimates ◽  
Class Iii ◽  
Class Iii Obesity ◽  
Total Body

Abstract Purpose To compare methods of estimating vancomycin volume of distribution (V) in adults with class III obesity. Methods A retrospective, multicenter pharmacokinetic analysis of adults treated with vancomycin and monitored through measurement of peak and trough concentrations was performed. Individual pharmacokinetic parameter estimates were obtained via maximum a posteriori Bayesian analysis. The relationship between V and body weight was assessed using linear regression. Mean bias and root-mean-square error (RMSE) were calculated to assess the precision of multiple methods of estimating V. Results Of 241 patients included in the study sample, 159 (66.0%) had a BMI of 40.0–49.9 kg/m2, and 82 (34.0%) had a BMI of ≥50.0 kg/m2. The median (5th, 95th percentile) weight of patients was 136 (103, 204) kg, and baseline characteristics were similar between BMI groups. The mean ± S.D. V was lower in patients with a BMI of 40.0–49.9 kg/m2 than in those with a BMI of ≥50.0 kg/m2 (72.4 ± 19.6 L versus 79.3 ± 20.6 L, p = 0.009); however, body size poorly predicted V in regression analyses (R2 < 0.20). A fixed estimate of V (75 L) or use of 0.52 L/kg by total body weight yielded similar bias and error in this population. Conclusion Results of the largest analysis of vancomycin V in class III obesity to date indicated that use of a fixed V value (75 L) and use of a TBW-based estimate (0.52 L/kg) for estimation of vancomycin V in patients with a BMI of ≥40.0 kg/m2 have similar bias. Two postdistribution vancomycin concentrations are needed to accurately determine patient-specific pharmacokinetic parameters, estimate AUC, and improve the precision of vancomycin dosing in this patient population.

Comparison of epsilon aminocaproic acid and tranexamic acid in pediatric cardiac surgery

2004 ◽  
Vol 18 (2) ◽  
pp. 141-143 ◽  
Author(s):  
Sandeep Chauhan ◽  
Sambhu N Das ◽  
Akshay Bisoi ◽  
Shailaja Kale ◽  
Usha Kiran
Keyword(s):  
Cardiac Surgery ◽  
Tranexamic Acid ◽  
Aminocaproic Acid ◽  
Pediatric Cardiac Surgery ◽  
Epsilon Aminocaproic Acid

Zalcitabine Population Pharmacokinetics: Application of Radioimmunoassay

1998 ◽  
Vol 42 (2) ◽  
pp. 409-413 ◽  
Author(s):  
John M. Adams ◽  
Mark J. Shelton ◽  
Ross G. Hewitt ◽  
Mary DeRemer ◽  
Robin DiFrancesco ◽  
...  
Keyword(s):  
Population Pharmacokinetics ◽  
Information Age ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Oral Clearance ◽  
Standard Curve ◽  
Immunodeficiency Virus ◽  
Traditional Approaches

ABSTRACT Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84 ± 1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6 ± 7.13 years), sex, weight (79.1 ± 15.0 kg), and estimated creatinine clearance (89.1 ± 21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters (4). The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.

scholarly journals Population Pharmacokinetics of Nevirapine, Zidovudine, and Didanosine in Human Immunodeficiency Virus-Infected Patients

1999 ◽  
Vol 43 (1) ◽  
pp. 121-128 ◽  
Author(s):  
Xiao-Jian Zhou ◽  
Lewis B. Sheiner ◽  
Richard T. D’Aquila ◽  
Michael D. Hughes ◽  
Martin S. Hirsch ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Population Pharmacokinetics ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Zero Order ◽  
Triple Combination ◽  
Entire Study ◽  
First Order ◽  
Immunodeficiency Virus

ABSTRACT The population pharmacokinetics of nevirapine (NVP), zidovudine (ZDV), and didanosine (ddI) were evaluated in a total of 175 patients infected with human immunodeficiency virus randomized to receive either a double combination of ZDV plus ddI or a triple combination of NVP plus ZDV plus ddI as a substudy of the AIDS Clinical Trials Group Protocol 241. Levels (approximating 3.5 determinations/patient) of the three drugs in plasma were measured during 44 of a total 48 weeks of study treatment, and a set of potential covariates was available for nonlinear mixed-effect modeling analysis. A one-compartment model with zero-order input and first-order elimination was fitted to the NVP data. Individual oral clearance (CL) and volume of distribution (V) averaged 0.0533 liters/h/kg of body weight and 1.17 liters/kg, respectively. Gender was the only covariate which significantly correlated with the CL of NVP. ZDV and ddI data were described by a two-compartment model with zero-order input and first-order elimination. Individual mean oral CL,V SS (volume of distribution at steady state), and V of ZDV were 1.84 liters/h/kg and 6.68 and 2.67 liters/kg, respectively, with body weight and age as correlates of CL and body weight as a correlate of V SS. The average individual oral CL, V SS, andV of ddI were 1.64 liters/h/kg and 3.56 and 2.74 liters/kg, respectively, with body weight as a significant correlate of both CL and V SS. The relative bioavailability (F) of ZDV and ddI in the triple combination compared to that in the double combination was also evaluated. No significant effects of the combination regimens on the F of ddI were detected (F TRIPLE = 1.05 andF DOUBLE = 1 by definition), but theF of ZDV was markedly reduced by the triple combination, being only 67.7% of that of the double combination. Large (>50%) intraindividual variability was associated with both ZDV and ddI pharmacokinetics. Individual cumulative area under the plasma drug level-time curve of the three drugs was calculated for the entire study period as a measure of drug exposure based on the individual data and the final-model estimates of structural and statistical parameters.

Pharmacokinetics of Tranexamic Acid in Neonates, Infants, and Children Undergoing Cardiac Surgery with Cardiopulmonary Bypass

2015 ◽  
Vol 122 (4) ◽  
pp. 746-758 ◽  
Author(s):  
Mark C. Wesley ◽  
Luis M. Pereira ◽  
Laurie A. Scharp ◽  
Sitaram M. Emani ◽  
Francis X. McGowan ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Young Children ◽  
Tranexamic Acid ◽  
High Performance ◽  
Structural Model ◽  
Heart Defects ◽  
Circulatory Arrest ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
First Time

Abstract Background: Tranexamic acid (TXA) is one of the most commonly used antifibrinolytic medications in children undergoing repair of congenital heart defects. However, a pharmacokinetics analysis of TXA has never been performed in neonates or young children undergoing complex cardiac surgeries using cardiopulmonary bypass, hypothermia, circulatory arrest, and ultrafiltration. A comprehensive pharmacokinetics study was performed in this patient population. Methods: Fifty-five patients ranging from 2 days through 4 yr old were categorized into three groups: children less than 2 months old, infants 2 months to 1 yr old, and children greater than 1 yr old and weighing up to 20 kg. TXA was given as a bolus of 100 mg/kg followed by an infusion of 10 mg · kg−1 · h−1 throughout the surgery. A dose of 100 mg/kg was placed in the cardiopulmonary bypass prime. A total of 16 to 18 samples were obtained from all patients throughout surgery. Plasma TXA concentrations were measured by high-performance liquid chromatography and modeled under a nonlinear mixed-effects framework with a two-compartment structural model. Results: Cardiopulmonary bypass had a statistically significant impact on all pharmacokinetic parameters. Age was a better covariate than body weight, affecting both the distribution and the elimination of TXA. However, weight performed well in some cases. Other covariates including body surface area, pump prime volume, ultrafiltrate volume, and body temperature did not improve the model. Conclusions: This TXA pharmacokinetic analysis is reported for the first time in neonates and young children undergoing complex cardiac surgeries with cardiopulmonary bypass. Dosing recommendations are provided as guidance for maintaining desired target concentrations.

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