Barriers and Challenges in Performing Pharmacokinetic Studies to Inform Dosing in the Neonatal Population

O’Hara, Kate; Martin, Jennifer H.; Schneider, Jennifer

doi:10.3390/pharmacy8010016

Cited by 12 publications

(14 citation statements)

References 24 publications

(39 reference statements)

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“…Strengths of our trial include a low loss to follow-up, standardised observational data, a high ascertainment of PK samples and robust timing and dosing information—a logistically challenging exercise in neonates in any setting. 49 Total observation days for neonates in both treatment arms were similar and sufficient number of neonates with available day 2 plasma sodium samples and complete sets of four PK samples contributed to this analysis, despite unbalanced losses due to consent withdrawals, loss to follow-up or deaths.…”

Section: Discussionmentioning

confidence: 99%

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload

et al. 2022

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ObjectiveTo assess pharmacokinetics and changes to sodium levels in addition to adverse events (AEs) associated with fosfomycin among neonates with clinical sepsis.DesignA single-centre open-label randomised controlled trial.SettingKilifi County Hospital, Kenya.Patients120 neonates aged ≤28 days admitted being treated with standard-of-care (SOC) antibiotics for sepsis: ampicillin and gentamicin between March 2018 and February 2019.InterventionWe randomly assigned half the participants to receive additional intravenous then oral fosfomycin at 100 mg/kg two times per day for up to 7 days (SOC-F) and followed up for 28 days.Main outcome(s) and measure(s)Serum sodium, AEs and fosfomycin pharmacokinetics.Results61 and 59 infants aged 0–23 days were assigned to SOC-F and SOC, respectively. There was no evidence of impact of fosfomycin on serum sodium or gastrointestinal side effects. We observed 35 AEs among 25 SOC-F participants and 50 AEs among 34 SOC participants during 1560 and 1565 infant-days observation, respectively (2.2 vs 3.2 events/100 infant-days; incidence rate difference −0.95 events/100 infant-days (95% CI −2.1 to 0.20)). Four SOC-F and 3 SOC participants died. From 238 pharmacokinetic samples, modelling suggests an intravenous dose of 150 mg/kg two times per day is required for pharmacodynamic target attainment in most children, reduced to 100 mg/kg two times per day in neonates aged <7 days or weighing <1500 g.Conclusion and relevanceFosfomycin offers potential as an affordable regimen with a simple dosing schedule for neonatal sepsis. Further research on its safety is needed in larger cohorts of hospitalised neonates, including very preterm neonates or those critically ill. Resistance suppression would only be achieved for the most sensitive of organisms so fosfomycin is recommended to be used in combination with another antimicrobial.Trial registration numberNCT03453177.

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Section: Discussionmentioning

confidence: 99%

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload

et al. 2022

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“…Due to the stressful situation of becoming a parent to a premature child, the required informed parental consent for neonates participating in research, can be difficult to obtain. The process may require repeated discussions with the families, and thus complicate recruitment for studies during the first hours/days of life ( O’Hara et al, 2020 ).…”

Section: Challenges In Pharmacokinetic Studies In Premature Neonatesmentioning

confidence: 99%

“…Fortunately, relatively few children are born very or extremely preterm, but the scarcity of premature neonates makes it challenging to include this population in PK studies. Traditional PK study designs involve multiple blood samples at fixed intervals and generally require the same number of samples from all subjects taken at the same time ( O’Hara et al, 2020 ). This approach presents practical difficulties in preterm neonates, as repeated blood sampling quickly exceeds the regulated ( EMA, 2018 ; Barker et al, 2018 ) maximum of 1% at any one time, or 3% within 1 month, amounting to 400 µl or 1.2 ml respectively for a neonate weighing 500 g. Also, the sampling procedure may prove challenging, as even something as mundane as drawing blood often requires experience in the extremely preterm children.…”

Section: Challenges In Pharmacokinetic Studies In Premature Neonatesmentioning

confidence: 99%

The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children

et al. 2022

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The limit for possible survival after extremely preterm birth has steadily improved and consequently, more premature neonates with increasingly lower gestational age at birth now require care. This specialized care often include intensive pharmacological treatment, yet there is currently insufficient knowledge of gestational age dependent differences in drug metabolism. This potentially puts the preterm neonates at risk of receiving sub-optimal drug doses with a subsequent increased risk of adverse or insufficient drug effects, and often pediatricians are forced to prescribe medication as off-label or even off-science. In this review, we present some of the particularities of drug disposition and metabolism in preterm neonates. We highlight the challenges in pharmacometrics studies on hepatic drug metabolism in preterm and particularly extremely (less than 28 weeks of gestation) preterm neonates by conducting a scoping review of published literature. We find that >40% of included studies failed to report a clear distinction between term and preterm children in the presentation of results making direct interpretation for preterm neonates difficult. We present summarized findings of pharmacokinetic studies done on the major CYP sub-systems, but formal meta analyses were not possible due the overall heterogeneous approaches to measuring the phase I and II pathways metabolism in preterm neonates, often with use of opportunistic sampling. We find this to be a testament to the practical and ethical challenges in measuring pharmacokinetic activity in preterm neonates. The future calls for optimized designs in pharmacometrics studies, including PK/PD modeling-methods and other sample reducing techniques. Future studies should also preferably be a collaboration between neonatologists and clinical pharmacologists.

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“…Population pharmacokinetic (popPK) analysis is a practical method to describe and predict blood concentrations in paediatric patients 19–22 . The most important issue in model evaluation is whether the established model can predict the pharmacokinetics in a prospective study or can be extrapolated to the patients at other institutions, particularly when the purpose of modelling is prediction of optimal individual dose 23 .…”

Section: Introductionmentioning

confidence: 99%

External evaluation of the predictive performance of seven population pharmacokinetic models for phenobarbital in neonates

Ryu

Jung

Jiao

et al. 2021

Brit J Clinical Pharma

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Aim Several studies have reported population pharmacokinetic models for phenobarbital (PB), but the predictive performance of these models has not been well documented. This study aims to do external evaluation of the predictive performance in published pharmacokinetic models. Methods Therapeutic drug monitoring data collected in neonates and young infants treated with PB for seizure control was used for external evaluation. A literature review was conducted through PubMed to identify population pharmacokinetic models. Prediction‐ and simulation‐based diagnostics, and Bayesian forecasting were performed for external evaluation. The incorporation of allometric scaling for body size and maturation factors into the published models was also tested for prediction improvement. Results A total of 79 serum concentrations from 28 subjects were included in the external dataset. Seven population pharmacokinetic studies of PB were identified as relevant in the literature search and included for our evaluation. The model by Voller et al showed the best performance concerning prediction‐based evaluation. In simulation‐based analyses, the normalized prediction distribution error of two models (those of Shellhaas et al and Marsot et al) obeyed a normal distribution. Bayesian forecasting with more than one observation improved predictive capability. Incorporation of both allometric size scaling and maturation function generally enhanced the predictive performance, with improvement as observed in the model of Vucicevic et al. Conclusions The predictive performance of published pharmacokinetic models of PB was diverse. Bayesian forecasting and incorporation of both size and maturation factors could improve the predictability of the models for neonates.

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Barriers and Challenges in Performing Pharmacokinetic Studies to Inform Dosing in the Neonatal Population

Cited by 12 publications

References 24 publications

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload

Randomised controlled trial of fosfomycin in neonatal sepsis: pharmacokinetics and safety in relation to sodium overload

The Blind Spot of Pharmacology: A Scoping Review of Drug Metabolism in Prematurely Born Children

External evaluation of the predictive performance of seven population pharmacokinetic models for phenobarbital in neonates

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