A Predictive Pharmacokinetic/Pharmacodynamic Model of Fentanyl for Analgesia/Sedation in Neonates Based on a Semi-Physiologic Approach

Encinas, Esther; Calvo, Rosario; Lukas, John C.; Vozmediano, Valvanera; Rodríguez, M.; Súárez, Eduardo Viñuela

doi:10.1007/s40272-013-0029-1

Cited by 33 publications

(20 citation statements)

References 50 publications

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“…This pragmatic PK design represents an efficient approach to further study of the clinical and genetic factors contributing to individual variability in drug exposure and response in children. These data may also be valuable for validation of semi‐physiologic models , another potential approach to improve paediatric dosing.…”

Section: Discussionmentioning

confidence: 99%

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

Driest

Marshall

Hachey

et al. 2016

Brit J Clinical Pharma

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AIMSOne barrier contributing to the lack of pharmacokinetic (PK) data in paediatric populations is the need for serial sampling. Analysis of clinically obtained specimens and data may overcome this barrier. To add evidence for the feasibility of this approach, we sought to determine PK parameters for fentanyl in children after cardiac surgery using specimens and data generated in the course of clinical care, without collecting additional blood samples. METHODSWe measured fentanyl concentrations in plasma from leftover clinically-obtained specimens in 130 paediatric cardiac surgery patients and successfully generated a PK dataset using drug dosing data extracted from electronic medical records. Using a population PK approach, we estimated PK parameters for this population, assessed model goodness-of-fit and internal model validation, and performed subset data analyses. Through simulation studies, we compared predicted fentanyl concentrations using model-driven weight-adjusted per kg vs. fixed per kg fentanyl dosing. RESULTSFentanyl clearance for a 6.4 kg child, the median weight in our cohort, is 5.7 l h -1 (2.2-9.2 l h -1 ), similar to values found in prior formal PK studies. Model assessment and subset analyses indicated the model adequately fit the data. Of the covariates studied, only weight significantly impacted fentanyl kinetics, but substantial inter-individual variability remained. In simulation studies, model-driven weight-adjusted per kg fentanyl dosing led to more consistent therapeutic fentanyl concentrations than fixed per kg dosing. CONCLUSIONSWe show here that population PK modelling using sparse remnant samples and electronic medical records data provides a powerful tool for assessment of drug kinetics and generation of individualized dosing regimens.

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Section: Discussionmentioning

confidence: 99%

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

Driest

Marshall

Hachey

et al. 2016

Brit J Clinical Pharma

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“…Data on the PK of fentanyl in preterm infants born before 32 weeks of gestation are sparse11 12 while few studies report on term neonates 13–15. In adults, fentanyl is mainly cleared by hepatic biotransformation via cytochrome P450 (CYP) 3A4 16–18.…”

Section: Introductionmentioning

confidence: 99%

Rapidly maturing fentanyl clearance in preterm neonates

Völler

Flint

Andriessen

et al. 2019

Arch Dis Child Fetal Neonatal Ed

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BackgroundFentanyl is frequently used off-label in preterm newborns. Due to very limited pharmacokinetic and pharmacodynamic data, fentanyl dosing is mostly based on bodyweight. This study describes the maturation of the pharmacokinetics in preterm neonates born before 32 weeks of gestation.Methods442 plasma samples from 98 preterm neonates (median gestational age: 26.9 (range 23.9–31.9) weeks, postnatal age: 3 (range 0–68) days, bodyweight 1.00 (range 0.39–2.37) kg) were collected in an opportunistic trial and fentanyl plasma levels were determined. NONMEM V.7.3 was used to develop a population pharmacokinetic model and to perform simulations.ResultsFentanyl pharmacokinetics was best described by a two-compartment model. A pronounced non-linear influence of postnatal and gestational age on clearance was identified. Clearance (L/hour/kg) increased threefold, 1.3-fold and 1.01-fold in the first, second and third weeks of life, respectively. In addition, clearance (L/hour/kg) was 1.4-fold and 1.7-fold higher in case of a gestational age of 28 and 31 weeks, respectively, compared with 25 weeks. Volume of distribution changed linearly with bodyweight and was 8.7 L/kg. To achieve similar exposure across the entire population, a continuous infusion (µg/kg/hour) dose should be reduced by 50% and 25% in preterm neonates with a postnatal age of 0–4 days and 5–9 days in comparison to 10 days and older.ConclusionBecause of low clearance, bodyweight-based dosages may result in fentanyl accumulation in neonates with the lowest postnatal and gestational ages which may require dose reduction. Together with additional information on the pharmacodynamics, the results of this study can be used to guide dosing.

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“…However, FEN administration is not indicated in infants (i.e., below 2 years of age) according to the manufacturer's product license, and the drug is therefore used off‐label in this population. In order to increase the knowledge on the product within this context and to try to reduce the degree of empiricism currently associated with the establishment of dosing regimens in this population, a maturation‐physiology‐based predictive pharmacokinetic/pharmacodynamic (PK/PD) model for fentanyl in neonatal care was built . The performance of a PK/PD study in a suitable animal species was subsequently deemed convenient, as a complement and preliminary confirmation to the developed theoretical model.…”

Section: Introductionmentioning

confidence: 99%

“…In order to increase the knowledge on the product within this context and to try to reduce the degree of empiricism currently associated with the establishment of dosing regimens in this population, a maturation-physiology-based predictive pharmacokinetic/pharmacodynamic (PK/PD) model for fentanyl in neonatal care was built. [4] The performance of a PK/PD study in a suitable animal species was subsequently deemed convenient, as a complement and preliminary confirmation to the developed theoretical model. Concretely, the newborn piglet was considered a representative model of FEN behaviour in neonates because many of its anatomical and physiological characteristics more closely resemble those of humans than other non-primate species, [5,6] as supported by the frequent use of preterm and term neonate pigs in paediatric research.…”

Section: Introductionmentioning

confidence: 99%

Quantitative determination of fentanyl in newborn pig plasma and cerebrospinal fluid samples by HPLC‐MS/MS

Blanco

Encinas

González

et al. 2015

Drug Testing and Analysis

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In this study, a selective and sensitive high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method requiring low sample volume (≤100 μL) was developed and validated for the quantitative determination of the opioid drug fentanyl in plasma and cerebrospinal fluid (CSF). A protein precipitation extraction with acetonitrile was used for plasma samples whereas CSF samples were injected directly on the HPLC column. Fentanyl and (13) C6 -fentanyl (Internal Standard) were analyzed in an electrospray ionization source in positive mode, with multiple reaction monitoring (MRM) of the transitions m/z 337.0/188.0 and m/z 337.0/105.0 for quantification and confirmation of fentanyl, and m/z 343.0/188.0 for (13) C6 -fentanyl. The respective lowest limits of quantification for plasma and CSF were 0.2 and 0.25 ng/mL. Intra- and inter-assay precision and accuracy did not exceed 15%, in accordance with bioanalytical validation guidelines. The described analytical method was proven to be robust and was successfully applied to the determination of fentanyl in plasma and CSF samples from a pharmacokinetic and pharmacodynamic study in newborn piglets receiving intravenous fentanyl (5 µg/kg bolus immediately followed by a 90-min infusion of 3 µg/kg/h).

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A Predictive Pharmacokinetic/Pharmacodynamic Model of Fentanyl for Analgesia/Sedation in Neonates Based on a Semi-Physiologic Approach

Cited by 33 publications

References 50 publications

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

Pragmatic pharmacology: population pharmacokinetic analysis of fentanyl using remnant samples from children after cardiac surgery

Rapidly maturing fentanyl clearance in preterm neonates

Quantitative determination of fentanyl in newborn pig plasma and cerebrospinal fluid samples by HPLC‐MS/MS

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