Dosing in neonates: special considerations in physiology and trial design

Ku, Lawrence; Smith, P. Brian

doi:10.1038/pr.2014.143

Cited by 93 publications

(75 citation statements)

References 70 publications

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“…This study employed scavenged PK sampling, which is a minimal-risk approach that uses leftover blood collected in the course of routine clinical care that would otherwise be discarded (15). The scavenged samples were as informative as the scheduled samples and did not bias parameter estimates.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Momper

Capparelli

Wade

et al. 2016

Antimicrob Agents Chemother

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Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

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Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Momper

Capparelli

Wade

et al. 2016

Antimicrob Agents Chemother

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“…Furthermore, ocular dosing is not weight adjusted and, therefore, pediatric patients are particularly vulnerable as drug metabolism is reduced in the young and/or an immature blood–brain barrier may be present. Contrary to the case of adults, pharmacokinetic–pharmacodynamic studies in pediatrics are extremely rare due to ethics and other aspects such as blood sampling 23. In particular, infants differ in their physiology, leading to altered pharmacokinetics and pharmacodynamics of a drug.…”

Section: Introductionmentioning

confidence: 99%

Systemic side effects of eye drops: a pharmacokinetic perspective

Farkouh¹,

Frigo²,

Czejka

2016

OPTH

175

131

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When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amounts can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concentration of active ingredients in such medicinal preparations is usually very high, so that despite the correct application of the recommended dose, considerable amounts may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not weight adjusted and physiological development (eg, liver status) differs from that of adults. There is a lack of information about pediatric dosing in the current literature. This review summarizes the most important clinically relevant systemic side effects that may occur during ophthalmic eye treatments. In this review, we discuss general pharmacokinetic considerations as well as the advantages, disadvantages, and consequences of administering drugs from some important drug groups to the eye.

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“…The renin-angiotensin system plays a crucial role during nephrogenesis, which does not complete until 34 weeks’ gestational age [25, 26]. Consequently, antagonism of this system prior to completion of nephrogenesis by ACE inhibitors such as enalapril can lead to acute fetal and neonatal renal dysfunction, which can result in hypotension, renal failure, anuria, and death [3, 5, 27–31].…”

Section: Discussionmentioning

confidence: 99%

Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit

Zimmerman

Benjamin

et al. 2016

Pediatr Cardiol

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Enalapril is used to treat hypertension and congestive heart failure in infants. However, enalapril is not labeled for neonates, and safety data in infants are sparse. To evaluate the safety of enalapril in young infants, we conducted a retrospective cohort study of infants who were exposed to enalapril in the first 120 days of life and were cared for in 348 neonatal intensive care units from 1997–2012. We determined the proportion of exposed infants who developed adverse events, including death, hypotension requiring pressors, hyperkalemia, and elevated serum creatinine. Using multivariable logistic regression, we examined risk factors for adverse events, including postnatal age at first exposure, exposure duration, gestational age group, small for gestational age status, race, sex, 5-minute Apgar score, and inborn status. Of a cohort of 887,910 infants, 662 infants (0.07%) were exposed to enalapril. Among exposed infants, 142 infants (21%) suffered an adverse event. The most common adverse event was hyperkalemia (13%), followed by elevated serum creatinine (5%), hypotension (4%), and death (0.5%). Significant risk factors for adverse events included postnatal age <30 days at first exposure and longer exposure duration. This study is the largest to date examining the safety of enalapril in young term and preterm infants without significant structural cardiac disease.

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Dosing in neonates: special considerations in physiology and trial design

Cited by 93 publications

References 70 publications

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Systemic side effects of eye drops: a pharmacokinetic perspective

Safety of Enalapril in Infants Admitted to the Neonatal Intensive Care Unit

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