scholarly journals Fluconazole Population Pharmacokinetics and Dosing for Prevention and Treatment of Invasive Candidiasis in Children Supported with Extracorporeal Membrane Oxygenation

2015 ◽  
Vol 59 (7) ◽  
pp. 3935-3943 ◽  
Author(s):  
Kevin M. Watt ◽  
Daniel Gonzalez ◽  
Daniel K. Benjamin ◽  
Kim L. R. Brouwer ◽  
Kelly C. Wade ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Mixed Effect ◽  
Final Model ◽  
Content Type ◽  
Membrane Oxygenation ◽  
Nonlinear Mixed Effect ◽  
Nonlinear Mixed Effect Modeling ◽  
Drug Pharmacokinetics

ABSTRACTCandidainfections are a leading cause of infectious disease-related death in children supported by extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK); thus, standard fluconazole dosing may result in suboptimal drug exposures. The objective of our study was to determine the PK of fluconazole in children on ECMO. Forty children with 367 PK samples were included in the analysis. The PK data were analyzed using nonlinear mixed-effect modeling (NONMEM). A one-compartment model best described the data. Weight was included in the base model for clearance (CL) and volume of distribution (V). The final model included the effect of serum creatinine (SCR) level on CL and the effect of ECMO onVas follows: CL (in liters per hour) = 0.019 × weight × (SCR/0.4)−0.29× exp(ηCL) andV(in liters) = 0.93 × weight × 1.4ECMO× exp(ηV). The fluconazoleVwas increased in children supported by ECMO. Consequently, children on ECMO require a higher fluconazole loading dose for prophylaxis (12 mg/kg of body weight) and treatment (35 mg/kg) paired with standard maintenance doses to achieve exposures similar to those of children not on ECMO.

scholarly journals 1540. A Population Pharmacokinetic Model for Vancomycin in Korean Patients Receiving Extracorporeal Membrane Oxygenation Therapy: A Prospective Study

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S562-S562
Author(s):  
Younghee Jung ◽  
Dong-Hwan Lee ◽  
Hyoung Soo Kim
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Creatinine Clearance ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Population Pharmacokinetic ◽  
Test Model ◽  
Mixed Effect ◽  
Korean Patients ◽  
Membrane Oxygenation ◽  
Population Pk

Abstract Background There is no literature on population pharmacokinetics (PK) of vancomycin in Korean patients receiving extracorporeal membrane oxygenation (ECMO) therapy. The aim of this study was to develop a population PK model for vancomycin in Korean ECMO patients. Methods We prospectively enrolled adult patients who were undergoing ECMO and receiving vancomycin from July 2018 to April 2019. After initial dose of vancomycin was administrated, serial blood samples (seven to nine times per patient) were drawn before the next dose. A population PK model for vancomycin was developed using a nonlinear mixed-effect modeling. Age, sex, creatinine clearance, and body weight were tested as potential covariates in the model. Model selection was based on log-likelihood test, model diagnostic plots, and clinical plausibility. Results Fourteen patients were included over the period. Ten received venovenous, three venoarterial, and one both type ECMO. Eleven were men and the median age was 54 (interquartile range 45–66.3). Mean estimated glomerular filtration rate (eGFR) was 69 ± 46 mL/minute/1.73m2 by the modification of diet in renal disease equation. A total of 123 vancomycin concentrations from the patients were included in the analysis. The population PK of vancomycin was best described by a two-compartment model with a proportional residual error model. The typical value (%between-subject variability) for total clearance was estimated to be 4.33 L/h (21.6%), central volume of distribution was 9.22 L, the intercompartmental clearance was 10.75 L/hr (34.9%) and the peripheral volume of distribution was 19.6 L (26.6%). The proportional residual variability was 8.81%. Creatinine clearance significantly influenced vancomycin clearance (CL). The proposed equation to estimate vancomycin clearance in Korean ECMO patients was CL = 4.33 + 0.199 × (eGFR – 56). Conclusion A two-compartment population PK model successfully describes vancomycin PK profiles in Korean ECMO patients. The model could be used to optimize the dosing regimen if more data become available from currently ongoing clinical study. Disclosures All authors: No reported disclosures.

scholarly journals Population Analysis of Weight-, Age-, and Sex-Related Differences in the Pharmacokinetics of Lopinavir in Children from Birth to 18 Years

2006 ◽  
Vol 50 (11) ◽  
pp. 3548-3555 ◽  
Author(s):  
Vincent Jullien ◽  
Saïk Urien ◽  
Déborah Hirt ◽  
Constance Delaugerre ◽  
Elisabeth Rey ◽  
...  
Keyword(s):  
Population Analysis ◽  
Combined Treatment ◽  
Elimination Rate ◽  
Compartment Model ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect ◽  
Nonlinear Mixed Effect Modeling ◽  
Age And Sex

ABSTRACT The pharmacokinetics of lopinavir were investigated by the use of a population approach performed with the nonlinear mixed effect modeling program NONMEM and 157 children ranging in age from 3 days to 18 years. The pharmacokinetics of lopinavir were well described by a one-compartment model in which the absorption and the elimination rate constants were equal. Typical population estimates of the apparent volume of distribution (V/F) and plasma clearance (CL/F) were 24.6 liters and 2.58 liters/h, respectively. The lopinavir V/F and CL/F were both related to body weight (BW), with an important increase in weight-normalized CL/F for the lowest BW. Combined treatment with lopinavir and nevirapine was found to increase the CL/F. The lopinavir CL/F was also age and sex related, as a 39% increase was observed after the age of 12 years for boys compared to the CL/F for girls. The consequences of these pharmacokinetic discrepancies and the necessity to modify the currently recommended dosage regimen should be further investigated.

scholarly journals Population pharmacokinetics of dapsone administered biweekly to human immunodeficiency virus-infected patients.

1996 ◽  
Vol 40 (12) ◽  
pp. 2743-2748 ◽  
Author(s):  
G Gatti ◽  
M Merighi ◽  
J Hossein ◽  
S Travaini ◽  
R Casazza ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Population Pharmacokinetics ◽  
Pneumocystis Carinii ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Mixed Effect ◽  
Nonlinear Mixed Effect ◽  
Immunodeficiency Virus ◽  
Nonlinear Mixed Effect Modeling ◽  
Post Hoc

The population pharmacokinetics of dapsone were examined in human immunodeficiency virus-infected patients receiving dapsone at a dosage of 100 mg twice weekly for the prevention of Pneumocystis carinii pneumonia. Nonlinear mixed-effect modeling was used to determine the best pharmacostatistical model for the data. A one-compartment open model with first-order absorption and elimination was used as the structural pharmacokinetic model. Several covariates were tested for their influence on pharmacokinetic parameters. Rifampin was found to increase the values of clearance/bioavailability (CL/F) and volume of distribution/ bioavailability (V/F) by approximately 70%. CL/F and V/F were 1.83 liters/h and 69.6 liters, respectively, for patients not taking rifampin. The effect of rifampin on the pharmacokinetic parameters of dapsone was appreciably less than expected on the basis of studies with healthy volunteers. Increased bilirubin levels were associated with a significant decrease in the absorption rate constant (Ka). However, this finding may be considered clinically irrelevant because the post hoc Bayesian estimates of Ka for patients with high bilirubin levels ( > 1.2 mg/dl) were at the lower bound of the values for patients with normal bilirubin levels. The value of Ka was 0.957 h-1 for a patient with a bilirubin level of 0.7 mg/dl. After inclusion of covariates in the model, the interpatient variability was 35% for CL/F, not significant for V/F, and 85% for Ka. Simulation of plasma concentration-versus-time curves indicated that the administration of 100 mg of dapsone biweekly is associated with sustained dapsone levels in the plasma of the majority of the patients. Dosage adjustments for patients concomitantly treated with rifampin may be necessary.

scholarly journals Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients

2018 ◽  
Vol 47 (04) ◽  
pp. 621-629 ◽  
Author(s):  
Lisette Schütte ◽  
Reinier van Hest ◽  
Sara Stoof ◽  
Frank Leebeek ◽  
Marjon Cnossen ◽  
...  
Keyword(s):  
Compartment Model ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Small Subset ◽  
Population Pharmacokinetic ◽  
Haemophilia A ◽  
Mixed Effect ◽  
Large Variability ◽  
Nonlinear Mixed Effect ◽  
Two Compartment Model

Background Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict. Objectives Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling. Patients and Methods Retrospective data of 128 nonsevere HA patients (age 7–75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reproducibility of FVIII:C response was defined as less than 25% difference in peak FVIII:C between administrations. Results A total of 623 FVIII:C measurements from 142 desmopressin administrations were available; 14 patients had received two administrations at different occasions. The FVIII:C time profile was best described by a two-compartment model with first-order absorption and elimination. Interindividual variability of the estimated baseline FVIII:C, central volume of distribution and clearance were 37, 43 and 50%, respectively. The most recently measured FVIII:C (FVIII-recent) was significantly associated with FVIII:C response to desmopressin (p < 0.001). Desmopressin administration resulted in an absolute FVIII:C increase of 0.47 IU/mL (median, interquartile range: 0.32–0.65 IU/mL, n = 142). FVIII:C response was reproducible in 6 out of 14 patients receiving two desmopressin administrations. Conclusion FVIII:C response to desmopressin in nonsevere HA patients was adequately described by a population PK model. Large variability in FVIII:C response was observed, which could only partially be explained by FVIII-recent. FVIII:C response was not reproducible in a small subset of patients. Therefore, monitoring FVIII:C around surgeries or bleeding might be considered. Research is needed to study this further.

scholarly journals Pharmacokinetics of vancomycin in critically ill infants undergoing extracorporeal membrane oxygenation.

1996 ◽  
Vol 40 (5) ◽  
pp. 1139-1142 ◽  
Author(s):  
R D Amaker ◽  
J T DiPiro ◽  
J Bhatia
Keyword(s):  
Renal Impairment ◽  
Extracorporeal Membrane Oxygenation ◽  
Half Life ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Published Data ◽  
Term Infants ◽  
Circulating Blood Volume ◽  
Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is a widely used therapy for neonates with respiratory failure. Because of sepsis, many of these infants require antibiotics like vancomycin during ECMO treatment. ECMO transiently alters renal function and increases the circulating blood volume by 75%. Initial vancomycin pharmacokinetics were determined in 12 infants undergoing ECMO to determine an adequate drug administration regimen. Vancomycin dosage was based on current recommendations for weight and gestational age. Pharmacokinetic parameters were determined by fitting the data to a two compartment model. This study yielded a mean steady-state volume of distribution of 1.1 +/- 0.5 (range, 0.6 to 2.1) liters/kg and a mean vancomycin clearance of 0.78 +/- 0.19 (range, 0.49 to 1.07) ml/min/kg. The mean vancomycin half-life was 16.9 +/- 9.5 (range, 8.8 to 42.9) h. Nomogram-calculated creatinine clearance was a significant predictor of vancomycin terminal rate constant and clearance. These data suggest alterations in the pharmacokinetics of vancomycin in infants on ECMO. With the goal of achieving vancomycin concentrations in serum above the MIC for the offending pathogen while using the least amount of the drug necessary, new administration guidelines for term infants without renal impairment undergoing ECMO should be 20 mg of vancomycin per kg at an interval of 24 h. With significant renal impairment, the interval should be extended on the basis of concentrations in serum. In comparison with previously published data, the neonates undergoing ECMO in our study demonstrated a much larger volume of distribution, a lower clearance, and consequently a longer vancomycin half-life.

scholarly journals Population Pharmacokinetics of Caspofungin among Extracorporeal Membrane Oxygenation Patients during the Postoperative Period of Lung Transplantation

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Qianlin Wang ◽  
Zhu Zhang ◽  
Donglin Liu ◽  
Wenqian Chen ◽  
Gang Cui ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Lung Transplantation ◽  
Postoperative Period ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Self Control ◽  
Control Group ◽  
Membrane Oxygenation ◽  
Population Pk ◽  
Before And After

ABSTRACT Little is known about the influence of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics (PK) of caspofungin. The aim of this study was to describe population PK of caspofungin in patients with and without ECMO during the postoperative period of lung transplantation (LTx) and to investigate covariates influencing caspofungin PK. We compared ECMO patients with non-ECMO patients, and patients before and after ECMO weaning as self-controls, to analyzed changes in caspofungin PK. Eight serial blood samples were collected from each patient for PK analysis. The population PK of caspofungin was described using nonlinear mixed-effects modeling. Twelve ECMO and 7 non-ECMO lung transplant recipients were enrolled in this study. None of the patients received renal replacement therapy during any part of the study period. The PK of caspofungin was best described by a two-compartment model. There were no significant differences in the PK parameters and concentrations of caspofungin among the ECMO, non-ECMO, and self-control group. In the final covariate model, we found that there was a significant association between the male gender and increased distribution volume, that a higher sequential organ failure assessment score was related to an increase in intercompartmental clearance, and that a longer operative time was related to an increase in clearance and the volume of distribution. ECMO did not have a significant impact on the PK of caspofungin in patients after LTx. Some factors were identified as statistically significant covariates related to the PK of caspofungin; however, their impact on clinical practice of caspofungin needs to be investigated further in more studies. (This study has been registered at ClinicalTrials.gov under identifier NCT03766282.)

scholarly journals P72 Maturation of sildenafil clearance in prematurely born infants with BPD associated pulmonary hypertension

2019 ◽  
Vol 104 (6) ◽  
pp. e47.1-e47
Author(s):  
H Nikrawesh ◽  
AGJ Engbers ◽  
S Völler ◽  
SHP Simons ◽  
BCP Koch ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Limited Information ◽  
Mixed Effect ◽  
Time Profiles ◽  
Nonlinear Mixed Effect ◽  
Postmenstrual Age ◽  
Oral Doses ◽  
Prematurely Born Infants

BackgroundSildenafil is used as an off-label treatment for bronchopulmonary dysplasia (BPD) associated pulmonary hypertension in prematurely born infants. As there is only limited information on the pharmacokinetics (PK) of sildenafil in this population, the aim of this study is to investigate the PK of sildenafil in prematurely born infants with BPD associated pulmonary hypertension.MethodIn this multicentre study, a population PK model for sildenafil in prematurely born infants was developed based on samples obtained using opportunistic sampling during clinical use of sildenafil. Data of seven subjects (42 plasma samples) were analysed by nonlinear mixed-effect modelling (NONMEM®7.3). Median (range) gestational age (GA) was 26.1 (24.1–27.6) weeks, current bodyweight 1960 (632–3157) grams, birthweight 635 (465–1125) grams and postnatal age (PNA) at start of therapy 64.9 (10.9–89) days. The median (range) treatment duration was 4.9 (1.6–13.1) weeks, with six subjects receiving oral doses of median 2.6 mg/kg/day (1.5–5.3) in three doses and one subject receiving oral and intravenous doses of 6.7 mg/kg/day in two doses.ResultsThe plasma concentration time profiles of sildenafil were best described by a one compartment model. Clearance (CL) and volume of distribution (Vd) for a child with a PNA of 64.9 days and bodyweight of 1.96 kg was 4.42 L/h ((RSE) 11%) and 29.5 L (32%), respectively. PNA was found to significantly influence CL, resulting in an increase of 10.7% in a week, and 43% in a month for a 65-day old infant. No other covariates (i.e. bodyweight, birthweight, GA, postmenstrual age and sex) were identified for CL or Vd.ConclusionIn this PK study, we characterised the pharmacokinetics of sildenafil in prematurely born infants and found that clearance increases with PNA. Due to the limited sample size in this study, further research in a larger population is needed to extend these findings.Disclosure(s)Nothing to disclose

Treatment of hyperammonemia using in-line renal replacement and hyperosmolar therapies within an extracorporeal membrane oxygenation circuit

Perfusion ◽  
2021 ◽  
pp. 026765912110359
Author(s):  
Alison Grazioli ◽  
Jamie E Podell ◽  
Aldo Iacono ◽  
Alexander Sasha Krupnik ◽  
Ronson J Madathil ◽  
...  
Keyword(s):  
Extracorporeal Membrane Oxygenation ◽  
Cerebral Edema ◽  
Urea Cycle ◽  
Rare Complication ◽  
Volume Of Distribution ◽  
Intermittent Hemodialysis ◽  
Treatment Goals ◽  
Continuous Venovenous Hemofiltration ◽  
Small Molecular Weight ◽  
Membrane Oxygenation

After orthotopic lung transplantation, hyperammonemia can be a rare complication secondary to infection by organisms that produce urease or inhibit the urea cycle. This can cause neurotoxicity, cerebral edema, and seizures. Ammonia is unique in that it has a large volume of distribution. However, it is also readily dialyzable given its small molecular weight. As such, removal of ammonia requires renal replacement modalities that can both rapidly remove ammonia from the plasma space and allow for continuous removal to prevent rebound accumulation from intracellular stores. Prevention of iatrogenic osmotic lowering in this setting is required to prevent worsening of cerebral edema. Herein, we describe use of sequential in-line renal replacement therapy using both intermittent hemodialysis and continuous venovenous hemofiltration within an extracorporeal membrane oxygenation circuit in conjunction with higher sodium dialysate and 7.5% hypertonic saline to achieve these treatment goals.

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.

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