Population pharmacokinetic analysis of ropivacaine and its metabolite 2′,6′-pipecoloxylidide from pooled data in neonates, infants, and children

Aarons, Leon; Sadler, Brian M.; Pitsiu, Maria; Sjövall, Jan; Henriksson, Jonas; Molnár, Valéria

doi:10.1093/bja/aer154

Cited by 41 publications

(28 citation statements)

References 33 publications

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“…Concentrations of AAG were shown to increase during the course of the surgery and appeared to plateau toward the end of the study period, which is consistent with previous studies . The magnitude of increase in AAG observed in this study is larger (approximately a fourfold median increase) compared to that observed by Booker et al (approximate twofold increase) and in the model developed by Aarons et al As a result of rich sampling at early time points, we observed a minor but consistent reduction in AAG concentrations in the immediate hours after the levobupivacaine, loading dose. This can be best described using an empirical precursor model, inhibiting AAG formation and simultaneously inducing precursor formation.…”

Section: Discussionsupporting

confidence: 91%

“…This was based on a population pharmacokinetic model of unbound levobupivacaine following a caudal injection of levobupivacaine 2 mg/kg given over 30 seconds, in infants undergoing sub‐umbilical surgery . The model was modified to account for time‐dependent changes in levels of AAG following surgery . It allowed the estimation of optimal sampling time points, limiting blood sample volumes in accordance with the WHO guidance .…”

Section: Methodsmentioning

confidence: 99%

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A study of the dosage and duration for levobupivacaine infusion by the caudal‐epidural route in infants aged 3‐6 months

Vashisht

Bendon

Okonkwo

et al. 2018

Pediatric Anesthesia

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Summary Background The local anesthetic, levobupivacaine, is the safer enantiomer of racemic bupivacaine. Present protocols for levobupivacaine are based on studies and pharmacokinetic modeling with racemic bupivacaine. Aims The aim is to investigate total serum levobupivacaine concentrations after a caudalepidural loading dose followed by a maintenance infusion over 48 hours in infants aged 3‐6 months. Methods The clinical trial was conducted in eight infants aged 3‐6 months, undergoing bladder exstrophy repair. Pharmacokinetic modeling allowed optimization of clinical sampling to measure total levobupivacaine and α1‐acid glycoprotein and prediction of the effect of α1‐acid glycoprotein on levobupivacaine plasma protein binding. Results The observed median total levobupivacaine serum concentration was 0.30 mg/L (range: 0.20‐0.70 mg/L) at 1 hour after the loading dose of 2 mg/kg. The median total levobupivacaine concentration after 47 hours of infusion, at 0.2 mg/kg/h, was 1.21 mg/L (0.07‐1.85 mg/L). Concentrations of α1‐acid glycoprotein were found to rise throughout the study period. Pharmacokinetic modeling suggested that unbound levobupivacaine quickly reached steady state at a concentration of approximately 0.03 mg/L. Conclusion The study allows the development of a pharmacokinetic model, combining levobupivacaine and α1‐acid glycoprotein data. Modeling indicates that unbound levobupivacaine quickly reaches steady state once the infusion is started. Simulations suggest that it may be possible to continue the infusion beyond 48 hours.

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Section: Discussionsupporting

confidence: 91%

Section: Methodsmentioning

confidence: 99%

A study of the dosage and duration for levobupivacaine infusion by the caudal‐epidural route in infants aged 3‐6 months

Vashisht

Bendon

Okonkwo

et al. 2018

Pediatric Anesthesia

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“…Mass balance was assumed for total, unbound, and bound drug concentrations in the plasma; an approach that has been widely applied in the target‐mediated drug disposition model for large molecules 30, 31. The model assumptions and parameterizations were different from the model by Aarons et al .,32 where the drug was assumed to exist solely as unbound status right after absorption, and the total drug was then calculated from unbound based on fast equilibrium‐binding.…”

Section: Discussionmentioning

confidence: 99%

Semi‐Mechanism‐Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib

Tong¹,

B²,

Gao³

et al. 2015

CPT Pharmacometrics Syst. Pharmacol.

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Vismodegib, approved for the treatment of advanced basal cell carcinoma, has shown unique pharmacokinetic (PK) nonlinearity and binding to α1‐acid glycoprotein (AAG) in humans. A semi‐mechanism‐based population pharmacokinetic (PopPK) model was developed from a meta‐dataset of 225 subjects enrolled in five clinical studies to quantitatively describe the clinical PK of vismodegib and identify sources of interindividual variability. Total and unbound vismodegib were analyzed simultaneously, together with time‐varying AAG data. The PK of vismodegib was adequately described by a one‐compartment model with first‐order absorption, first‐order elimination of unbound drug, and saturable binding to AAG with fast‐equilibrium. The variability of total vismodegib concentration at steady‐state was predominantly explained by the range of AAG level. The impact of AAG on unbound concentration was clinically insignificant. Various approaches were evaluated for model validation. The semi‐mechanism‐based PopPK model described herein provided insightful information on the nonlinear PK and has been utilized for various clinical applications.

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“…Using a mass balance principle, this model reproduced the protein binding process of ropivacaine. In previously used approaches, the binding site concentrations (AAG concentrations) did not affect free ropivacaine pharmacokinetics and were therefore unable to reproduce the decrease in free ropivacaine over time (Figure ). Our model accurately described the temporal changes in the unbound ropivacaine fraction (Figures , and ).…”

Section: Discussionmentioning

confidence: 99%

“…A prior distribution based on the work of Aarons et al . was introduced for K d . This prior followed a normal distribution with mean equal to 0.58 μ m and an SD of 0.05.…”

Section: Methodsmentioning

confidence: 99%

Population pharmacokinetic model of free and total ropivacaine after transversus abdominis plane nerve block in patients undergoing liver resection

Ollier

Héritier

Bonnet

et al. 2015

Brit J Clinical Pharma

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AIMSThe aim of this study was to develop a pharmacokinetic model in order to characterize the free and total ropivacaine concentrations after transversus abdominis plane block in a population of patients undergoing liver resection surgery. In particular, we evaluated the impact of the size of liver resection on ropivacaine pharmacokinetics. METHODSThis work is based on a single-centre, double-blinded, randomized, placebocontrolled study. Among the 39 patients included, 19 patients were randomized to the ropivacaine group. The free and total ropivacaine concentrations were measured in nine or 10 blood samples per patient. A pharmacokinetic model was built using a nonlinear mixed-effect modelling approach. RESULTSThe free ropivacaine concentrations remained under the previously published toxic threshold. A one-compartment model, including protein binding site with a first-order absorption, best described the data. The protein binding site concentration was considered as a latent variable. Bodyweight, the number of resected liver segments and postoperative fibrinogen evolution were, respectively, included in the calculation of the volume of distribution, clearance and binding site production rate. The resection of three or more liver segments was associated with a 53% decrease in the free ropivacaine clearance. CONCLUSIONSAlthough large liver resections were associated with lower free ropivacaine clearance, the ropivacaine pharmacokinetic profile remained within the safe range after this type of surgery. WHAT THIS STUDY ADDS• The free ropivacaine fraction is low after liver resection surgery (<2%).• The size of the liver resection affects the free ropivacaine clearance.• The pharmacokinetics of free and total ropivacaine could be analysed effectively even without α 1 -acid glycoprotein measurements. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Ropivacaine is highly bound to plasma proteins (α 1 -acid glycoprotein).• Ropivacaine is mainly metabolized by the liver.• Liver resection affects the protein binding and metabolism of ropivacaine.

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Population pharmacokinetic analysis of ropivacaine and its metabolite 2′,6′-pipecoloxylidide from pooled data in neonates, infants, and children

Abstract: Ropivacaine and PPX unbound clearance depends on body weight and age. The results support approved dose recommendations of ropivacaine for the paediatric population.

Cited by 41 publications

References 33 publications

A study of the dosage and duration for levobupivacaine infusion by the caudal‐epidural route in infants aged 3‐6 months

A study of the dosage and duration for levobupivacaine infusion by the caudal‐epidural route in infants aged 3‐6 months

Semi‐Mechanism‐Based Population Pharmacokinetic Modeling of the Hedgehog Pathway Inhibitor Vismodegib

Population pharmacokinetic model of free and total ropivacaine after transversus abdominis plane nerve block in patients undergoing liver resection

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