Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation.
Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable f...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 75; no. 10; pp. 1393 - 1405 |
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| Autores principales: | , , , , , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Oct2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=138590240&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 138590240 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Oct2019 vid: 75 iid: 10 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 138590240 138590240 144102203 138590240 10.1007/s00228-019-02708-y 138590240 ppf: 1393 ppct: 12 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation. aug: au: van Dijkman, Sven C. De Cock, Pieter A. J. G. Smets, Koenraad Decaluwe, Wim Smits, Anne Allegaert, Karel Vande Walle, Johan De Paepe, Peter Della Pasqua, Oscar affil: Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden, The Netherlands sug: subj: Adrenergic alpha-Agonists Pharmacokinetics Adrenergic alpha-Agonists Administration and Dosage Respiration, Artificial In Infancy and Childhood Dosage Calculation Drug Design Infant, Newborn Individualized Medicine Simulations Metabolic Clearance Rate Infant, Premature Pilot Studies Human Infant, Newborn: birth-1 month ab: Purpose: There is a need for alternative analgosedatives such as dexmedetomidine in neonates. Given the ethical and practical difficulties, protocol design for clinical trials in neonates should be carefully considered before implementation. Our objective was to identify a protocol design suitable for subsequent evaluation of the dosing requirements for dexmedetomidine in mechanically ventilated neonates. Methods: A published paediatric pharmacokinetic model was used to derive the dosing regimen for dexmedetomidine in a first-in-neonate study. Optimality criteria were applied to optimise the blood sampling schedule. The impact of sampling schedule optimisation on model parameter estimation was assessed by simulation and re-estimation procedures for different simulation scenarios. The optimised schedule was then implemented in a neonatal pilot study. Results: Parameter estimates were more precise and similarly accurate in the optimised scenarios, as compared to empirical sampling (normalised root mean square error: 1673.1% vs. 13,229.4% and relative error: 46.4% vs. 9.1%). Most importantly, protocol deviations from the optimal design still allowed reasonable parameter estimation. Data analysis from the pilot group (n = 6) confirmed the adequacy of the optimised trial protocol. Dexmedetomidine pharmacokinetics in term neonates was scaled using allometry and maturation, but results showed a 20% higher clearance in this population compared to initial estimates obtained by extrapolation from a slightly older paediatric population. Clearance for a typical neonate, with a post-menstrual age (PMA) of 40 weeks and weight 3.4 kg, was 2.92 L/h. Extension of the study with 11 additional subjects showed a further increased clearance in pre-term subjects with lower PMA. Conclusions: The use of optimal design in conjunction with simulation scenarios improved the accuracy and precision of the estimates of the parameters of interest, taking into account protocol deviations, which are often unavoidable in this event-prone population. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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