Population Pharmacokinetics of Digoxin in Pediatric Patients

Martín-Suárez, Ana; Falcão, Amílcar; Outeda, M.; Hernández, Fernando; González, María Catalina; Quero, M; Arranz, I.; Lanao, J. M.

doi:10.1097/00007691-200212000-00010

Cited by 10 publications

(21 citation statements)

References 7 publications

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“…It is well recognized that renal blood flow, the glomerular filtration rate, and tubular secretion change rapidly within the first year of life 6 . The correlation between some other covariates, such as body weight and age, with the pharmacokinetic (PK) parameters of many drugs is also suggested in the literature 7 , 8 . So there is good reason to believe that meropenem PK in pediatric patients is closely related with some potential covariates.…”

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confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Pediatric Patients

Kuti

et al. 2006

The Journal of Clinical Pharma

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Meropenem is a highly potent carbapenem antibiotic against gram-positive and gram-negative bacteria. Meropenem plasma concentration data from 99 pediatric patients (aged 0.08-17.3 years) were used to develop a population pharmacokinetic model. Pharmacokinetic analysis was performed using NONMEM with exponential interindividual variability and combinational residual error model. A 2-compartment model was found to fit the data best. Creatinine clearance and body weight were the most significant covariates explaining variabilities in meropenem pharmacokinetics among pediatric patients. The validated final model was used to predict meropenem plasma concentrations in 37 pediatric meningitis patients, receiving 40 mg/kg meropenem, who had minimum inhibitory concentration values of the causative pathogens and outcome available. Since the causative pathogens in all patients were eradicated, no break points for required exposure could be found. The microbiological outcomes indicate that the current clinical dosage regimen provides sufficient drug exposure to eradicate the pathogens commonly involved in pediatric meningitis.

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confidence: 99%

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Pediatric Patients

Kuti

et al. 2006

The Journal of Clinical Pharma

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“…10,19,20 This is quite logical as the renal function changes with age in neonates. 22 Such a relationship between age and digoxin clearance could not be observed in the current study.…”

Section: Discussionmentioning

confidence: 99%

Application of Two-Point Assay of Digoxin Serum Concentration in Studying Population Pharmacokinetics in Egyptian Pediatric Patients with Heart Failure: Does It Make Sense?

Desoky¹,

Madabushi

Amry

et al. 2005

American Journal of Therapeutics

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Digoxin pharmacokinetics (PK) was studied among a selected group of Egyptian pediatric patients (n = 40) with an age range of 0.33 to 15 years. All the patients had heart failure and were maintained on i.v. digoxin (10 microg/kg/d in 2 equal doses). For population PK analysis, 2 serum samples of digoxin were taken per patient. From 30 patients' trough (before the next dose) and 4 hours postdose samples were obtained, while in the other 10 patients, 0.5- and 6-hour postdose samples were taken. Serum concentrations were measured by fluorescence polarization immunoassay. PK modeling was performed using NONMEM software on log-transformed serum digoxin data. The best structural covariate-free model was a linear 2-compartment model with an exponential error model for intersubject variability and an additive model for intrasubject variability. Serum creatinine (SCR) was a significant covariate for clearance. The final population PK parameters were CL (L/h) = 0.388 - [0.78 x (SCR-0.6)], V1 (L/kg) = 1.38, Q (L/h/kg) = 0.48, V2 (L/kg) = 9.11, where CL is the total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, and Q is intercompartment clearance. A bootstrap resampling for internal validation achieved excellent agreement with the original data sets for PK parameters. In conclusion, 2 points of digoxin concentration allow good regression analysis for clearance-covariate relationship. The inclusion of SCR into the final model might allow better selection of initial maintenance dose of the drug. A prospective study on larger sample size of pediatric patients is recommended for clinical validation of the final model.

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“…Previous studies [1,2,7] reported that a one-compartment model and the first-order kinetics process could describe the time course of digoxin steady state concentrations in plasma. In this paper, a one-compartment open model was selected as a population structural PK model.…”

Section: Structural Pharmacokinetic Modelmentioning

confidence: 99%

“…Because of its low therapeutic index, narrow safety range and strong side effects, toxicity may also be caused by routine dosage [1][2][3][4] . Elderly patients with heart failure are more susceptible to toxicity because their impaired renal function may cause the clearance of digoxin to decrease.…”

Section: Introductionmentioning

confidence: 99%

“…approved by the US fDa in 1999, NONMEM [1][2][3][4][5][6][7][8] is the best model for clinical individualized medication. It was built on the basis of a combination of the classical pharmacokinetic www.nature.com/aps Zhou XD et al Acta Pharmacologica Sinica npg 113 of the 119 patients (95%) were suffering from varying degrees of congestive heart failure (Chf).…”

Section: Introductionmentioning

confidence: 99%

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Population pharmacokinetic model of digoxin in older Chinese patients and its application in clinical practice

et al. 2010

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Aim: To establish a population pharmacokinetic (PPK) model of digoxin in older Chinese patients to provide a reference for individual medication in clinical practice. Methods: Serum concentrations of digoxin and clinically related data including gender, age, weight (WT), serum creatinine (Cr), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), albumin (ALB), and co-administration were retrospectively collected from 119 older patients taking digoxin orally for more than 7 d. NONMEM software was used to get PPK parameter values, to set up a final model, and to assess the models in clinical practice. Results: Spironolactone (SPI), WT, and Cr markedly affected the clearance rate of digoxin. The final model formula is Cl/F=5.The population estimates for Cl/ F and V d /F were 5.9 L/h and 550 L, respectively. The interindividual variabilities (CV) were 49.0% for Cl/F and 94.3% for V d /F. The residual variability (SD) between observed and predicted concentrations was 0.365 μg/L. The difference between the objective function value and the primitive function value was less than 3.84 (P>0.05) by intra-validation. Clinical applications indicated that the percent of difference between the predicted concentrations estimated by the PPK final model and the observed concentrations were -4.3%−+25%. Correlation analysis displayed that there was a linear correlation between observated and predicted values (y=1.35x+0.39, r=0.9639, P<0.0001). Conclusion: The PPK final model of digoxin in older Chinese patients can be established using the NONMEM software, which can be applied in clinical practice.Keywords: digoxin; population pharmacokinetics; aging; retrospective studies; NONMEM Acta Pharmacologica Sinica advance (2010) 31: 753-758; doi: 10.1038/aps.2010.51 Original Article model, the fixed-effect model and the statistical model. The principle of the extended non-linear least squares was applied to estimate the population pharmacokinetic parameters using the patients' sparse plasma concentration data, pathological factors, physiological factors and coadministration. This paper aimed: 1) to build a population pharmacokinetic basic model of digoxin in 119 older Chinese patients; 2) to analyze the effects of fixed-effect factors such as weight, age, gender, hepatic and renal function, and concomitant medications on this model; 3) to establish the full regression model and the final model; and 4) to determine whether the final model is stable and reliable by intra-validation and clinical applications. Materials and methods Data sourcesRoutine clinical data were retrospectively collected from 119 older patients in the general hospital of the air force, PLa.

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Population Pharmacokinetics of Digoxin in Pediatric Patients

Cited by 10 publications

References 7 publications

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Pediatric Patients

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Pediatric Patients

Application of Two-Point Assay of Digoxin Serum Concentration in Studying Population Pharmacokinetics in Egyptian Pediatric Patients with Heart Failure: Does It Make Sense?

Population pharmacokinetic model of digoxin in older Chinese patients and its application in clinical practice

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