Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

Paradisis, Mary; Jiang, Xiaorui; McLachlan, Andrew J.; Evans, Nick; Kluckow, Martin; Osborn, David A

doi:10.1136/adc.2005.092817

Cited by 67 publications

(61 citation statements)

References 29 publications

(18 reference statements)

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“…We created 1,000 individual PK parameter value sets by simulating a PK model from Paradisis et al [8 ]with bootstrapped collected weights. Individual PK estimates were used in simulating time-concentration profiles with varied maintenance and loading doses.…”

Section: Methodsmentioning

confidence: 99%

“…Between-subject variability estimates were 24 and 21%, respectively. Body weight was a single covariate affecting both clearance and volume of distribution via allometric scaling [8]. …”

Section: Methodsmentioning

confidence: 99%

“…In a randomized double-blind study in a similar population that compared milrinone to placebo, a milrinone bolus of 75 μg/kg followed by 0.75 μg/kg/min infusion led to a 55% relative risk reduction for low cardiac output syndrome [6]. Based on the above data, two studies which addressed the optimal dosing of milrinone in term and preterm infants by Vogt [7] and Paradisis et al [8] targeted plasma concentrations in ranges of 100-300 ng/ml and 180-300 ng/ml, respectively. …”

Section: Introductionmentioning

confidence: 99%

“…According to Paradisis et al [8], the model-derived estimated half-life of milrinone is 10 h and clearance is 0.64 ml/kg/min in preterm neonates during the first day of life. The long half-life suggests the need for a loading dose to achieve therapeutic concentration within a reasonable time, while low clearance refers to possible accumulation of the drug.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion

Hallik

Tasa²,

Starkopf³

et al. 2016

Neonatology

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Background: Milrinone has been suggested as a possible first-line therapy for preterm neonates to prevent postligation cardiac syndrome (PLCS) through decreasing systemic vascular resistance and increasing cardiac contractility. The optimal dosing regimen, however, is not known. Objective: To model the dosing of milrinone in preterm infants for prevention of PLCS after surgical closure of patent ductus arteriosus (PDA). Methods: Milrinone time-concentration profiles were simulated for 1,000 subjects using the volume of distribution and clearance estimates based on one compartmental population pharmacokinetic model by Paradisis et al. [Arch Dis Child Fetal Neonatal Ed 2007;92:F204-F209]. Dose optimization was based on retrospectively collected demographic data from neonates undergoing PDA ligation in Estonian PICUs between 2012 and 2014 and existing pharmacodynamic data. The target plasma concentration was set at 150-200 ng/ml. Results: The simulation study useddemographic data from 31 neonates who underwent PDA ligation. The median postnatal age was 13 days (range: 3-29) and weight was 760 g (range: 500-2,351). With continuous infusion of milrinone 0.33 μg/kg/min, the proportion of subjects within the desired concentration range was 0% by 3 h, 36% by 6 h, and 61% by 8 h; 99% of subjects exceeded the range by 18 h. The maximum proportion of total simulated concentrations in the target range was attained with a bolus infusion of 0.73 μg/kg/min for 3 h followed by a 0.16-μg/kg/min maintenance infusion. Conclusion: Mathematical simulations suggest that in preterm neonates the plasma time-concentration profile of milrinone can be optimized with a slow loading dose followed by maintenance infusion.

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Section: Methodsmentioning

confidence: 99%

“…Between-subject variability estimates were 24 and 21%, respectively. Body weight was a single covariate affecting both clearance and volume of distribution via allometric scaling [8]. …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion

Hallik

Tasa²,

Starkopf³

et al. 2016

Neonatology

View full text Add to dashboard Cite

show abstract

“…16 In open label, dose escalation and pharmacokinetic studies, we established an appropriate milrinone regimen for very preterm babies. 17,18 We then tested this regimen in a randomized placebo-controlled trial with a view to preventing low SBF during the transitional period. 19 High-risk babies (mainly born before 28 weeks) were randomized to milrinone infusion (loading with 75 mg kg À1 h À1 for 3 h, maintained at 20 mg kg À1 h À1 until 18 h of age) or a placebo.…”

Section: Reducing Afterloadmentioning

confidence: 99%

Support of the preterm circulation: Keynote Address to the Fifth Evidence vs Experience Conference, Chicago, June 2008

Evans

2009

J Perinatol

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Hemodynamics is an area of neonatology that is marked more by what we do not know than what we do. What is clear is that it is much more complex than just measuring blood pressure (BP). Early postnatal preterm hemodynamic pathophysiology is characterized by low systemic blood flow (SBF), possibly relating to a mix of afterload compromise, left-to-right shunting through the unconstricted ductus and to the circulatory effects of ventilation. After B24 h of age, vasodilatation seems to be the dominant pathology. In the face of this complexity, a one-size-fits-all approach to treatment that will be applicable in a large clinical trial may prove elusive. The possibility of using a measure of both BP and SBF to target an appropriate treatment needs to be explored.

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The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow

Osborn

Paradisis

Evans

2007

Cochrane Database of Systematic Reviews

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Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

Abstract: Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology.

Cited by 67 publications

References 29 publications

Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion

Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion

Support of the preterm circulation: Keynote Address to the Fifth Evidence vs Experience Conference, Chicago, June 2008

The effect of inotropes on morbidity and mortality in preterm infants with low systemic or organ blood flow

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