Maintenance digoxin dosage and steady-state plasma concentration in infants and children

Hastreiter, Alois R.; Horst, Ronald L.; Voda, Carol; Chow-Tung, Elizabeth

doi:10.1016/s0022-3476(85)80636-3

Cited by 21 publications

(6 citation statements)

References 16 publications

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“…Although the volume of distribution (V ss ) estimated in the present study (9.82 L/kg) was comparable with that reported in earlier studies, 18 it was less than that estimated in the previous Egyptian study 5 (Vd: 18.8 L/kg) ( Table 2). The different route of digoxin administration (orally) and the kind of compartmental analysis (1-compartment model) in the previous Egyptian study may be responsible for this difference.…”

Section: Discussionsupporting

confidence: 83%

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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Section: Discussionsupporting

confidence: 83%

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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“…However, as the drug is mainly renally cleared, and glomerular filtration is still immature at birth, one would expect a lower body size-corrected clearance. This was indeed the case in preterm infants (<2.5 kg) whose digoxin bodyweight-corrected clearance was much lower than that of term infants (0.064 vs. 0.1 L/h/kg), in line with lower dosing recommendations for this age group [ 38 ]. Thus, in preterm newborns, both the glomerular filtration rate (GFR) and ABCB1 may be immature at birth, while in term infants ABCB1 activity may already be more mature and compensate for developmentally low GFR.…”

Section: Pharmacokinetic and Pharmacogenetic Studies Of Relevant Membmentioning

confidence: 77%

Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics

et al. 2015

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Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug–drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-015-0328-5) contains supplementary material, which is available to authorized users.

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“…To further investigate the ontogeny of biliary elimination of digoxin in premature neonates, a number of simulations were undertaken by applying the user-defined ontogeny to this pathway to recover the CL values reported clinically by Hastreiter et al (1985). Because the GA was not reported and only the weight ranges (,1.5 kg fu, fraction unbound in plasma; K in and K out , rate constants into and out of the additional compartment; Q gut , flow rate for overall delivery of drug to the gut enterocytes (depends on drug permeability and blood flow to villi); v ss , volume of distribution at steady-state; V sac , volume of an additional compartment.…”

Section: Pediatric Pbpk Modelingmentioning

confidence: 99%

How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

Johnson

Jamei

Rowland‐Yeo

2016

Drug Metabolism and Disposition

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Information on the developmental changes in biliary excretion (BE) of drugs is sparse. The aims of this study were to collate literature data on the pharmacokinetics of biliary excretion of drugs used in pediatrics and to apply a physiologically based pharmacokinetic (PBPK) model to predict their systemic clearance (CL) with a view to elucidating age-related changes in biliary excretion. Drug parameters for azithromycin, ceftriaxone, and digoxin administered intravenously and buprenorphine (intravenous and sublingual) were collated from the literature and used in the Simcyp Simulator to predict adult CL values, which were then validated against observed data. The change in CL with age was simulated in the pediatric model and compared with observed data; where necessary, the ontogeny function associated with BE was applied to recover the age-related CL. For azithromycin a fraction of adult BE activity of 15% was necessary to predict the CL in neonates (26 weeks gestational age) and 100% activity was apparent by 7 months. For ceftriaxone and digoxin full BE activity appeared to be present at term birth; for digoxin, an adult BE activity of 10% was needed to predict the CL in premature neonates (30 weeks gestational age). The CL of buprenorphine with age was described by the ontogeny of the major elimination pathways (CYP3A4 and UGT1A1) with no ontogeny assumed for the biliary component. Thus, the ontogeny of BE for all four drugs appears to be rapid and they attain adult levels at birth or within the first few months of postnatal age.

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Maintenance digoxin dosage and steady-state plasma concentration in infants and children

Cited by 21 publications

References 16 publications

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

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

Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics

How Does In Vivo Biliary Elimination of Drugs Change with Age? Evidence from In Vitro and Clinical Data Using a Systems Pharmacology Approach

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