Dopamine pharmacokinetics in critically ill newborn infants

Padbury, Jamés F.; Agata, Youtaro; Baylen, Barry G.; Ludlow, John K.; Polk, Daniel H.; Goldblatt, Eileen; Pescetti, John

doi:10.1016/s0022-3476(87)80176-2

Cited by 98 publications

(18 citation statements)

References 17 publications

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“…This finding is consistent with first-order kinetics of dopamine clearance in human newborn and adults, in which steady state concentration and plasma clearance rate did not change with the duration of infusion (21,22). Steady state CSF dopamine level was achieved fairly quickly in the preterm brain.…”

Section: Pharmacokinetics Of Dopaminesupporting

confidence: 85%

Preterm lambs given intravenous dopamine show increased dopamine in their cerebrospinal fluid

et al. 2014

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Section: Pharmacokinetics Of Dopaminesupporting

confidence: 85%

Preterm lambs given intravenous dopamine show increased dopamine in their cerebrospinal fluid

et al. 2014

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“…The use of dopamine has been shown to have a variable effect on cardiac output in these populations, with some patients having a concentration-dependent increase in cardiac output, whereas others show little response to infused dopamine. 43 These differences might be due to the variable baseline of cardiac output observed in patients. In the present study, cardiac output was increased by 50% in virtual subjects to assess the sensitivity on the PBPK modelpredicted morphine CL, based upon the finding that cardiac output increased 45-51% in neonatal patients that showed a cardiac response to dopamine.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, cardiac output was increased by 50% in virtual subjects to assess the sensitivity on the PBPK modelpredicted morphine CL, based upon the finding that cardiac output increased 45-51% in neonatal patients that showed a cardiac response to dopamine. 43 The cardiac output was also decreased to 50% in the performed sensitivity analysis, because quantified fractional reduction in renal blood flow, which is set at 19% (male subjects) and 17% (female subjects) of cardiac output in the Simcyp Simulator, was reported at 78%, 55%, and 63% of normal blood flow in adult patients with mild, moderate, and severe chronic heart failure, respectively. 44,45 Sensitivity of morphine CL to changes in cardiac output increased with age from 1 day old to 3 years old.…”

Section: Discussionmentioning

confidence: 99%

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

Emoto

Johnson

Neuhoff

et al. 2018

CPT Pharmacom & Syst Pharma

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Morphine has large pharmacokinetic variability, which is further complicated by developmental changes in neonates and small infants. The impacts of organic cation transporter 1 (OCT1) genotype and changes in blood‐flow on morphine clearance (CL) were previously demonstrated in children, whereas changes in UDP‐glucuronosyltransferase 2B7 (UGT2B7) activity showed a small effect. This study, targeting neonates and small infants, was designed to assess the influence of developmental changes in OCT1 and UGT2B7 protein expression and modified blood‐flow on morphine CL using physiologically based pharmacokinetic (PBPK) modeling. The implementation of these three age‐dependent factors into the pediatric system platform resulted in reasonable prediction for an age‐dependent increase in morphine CL in these populations. Sensitivity of morphine CL to changes in cardiac output increased with age up to 3 years, whereas sensitivity to changes in UGT2B7 activity decreased. This study suggests that morphine exhibits age‐dependent extraction, likely due to the developmental increase in OCT1 and UGT2B7 protein expression/activity and hepatic blood‐flow.

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“…Dopamine PK in critically ill children has been studied previously in children with a gestational age (range) of 27–42 weeks [200,201]. The mean (range) CL and V D of dopamine were reported as 115 mL/min/kg (62–168) and 1.8 L/kg (0.6–4) [200].…”

Section: Pharmacokinetic Studies In Critically Ill Childrenmentioning

confidence: 99%

Clinical Pharmacology Studies in Critically Ill Children

et al. 2016

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Developmental and physiological changes in children contribute to variation in drug disposition with age. Additionally, critically ill children suffer from various life-threatening conditions that can lead to pathophysiological alterations that further affect pharmacokinetics (PK). Some factors that can alter PK in this patient population include variability in tissue distribution caused by protein binding changes and fluid shifts, altered drug elimination due to organ dysfunction, and use of medical interventions that can affect drug disposition (e.g., extracorporeal membrane oxygenation and continuous renal replacement therapy). Performing clinical studies in critically ill children is challenging because there is large inter-subject variability in the severity and time course of organ dysfunction; some critical illnesses are rare, which can affect subject enrollment; and critically ill children usually have multiple organ failure, necessitating careful selection of a study design. As a result, drug dosing in critically ill children is often based on extrapolations from adults or non-critically ill children. Dedicated clinical studies in critically ill children are urgently needed to identify optimal dosing of drugs in this population. This review will summarize the effect of critical illness on pediatric PK, the challenges associated with performing studies in this vulnerable subpopulation, and the clinical PK studies performed to date for commonly used drugs.

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Dopamine pharmacokinetics in critically ill newborn infants

Cited by 98 publications

References 17 publications

Preterm lambs given intravenous dopamine show increased dopamine in their cerebrospinal fluid

Preterm lambs given intravenous dopamine show increased dopamine in their cerebrospinal fluid

PBPK Model of Morphine Incorporating Developmental Changes in Hepatic OCT1 and UGT2B7 Proteins to Explain the Variability in Clearances in Neonates and Small Infants

Clinical Pharmacology Studies in Critically Ill Children

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