Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

Morse, James D.; Anderson, Brian J.; Gastine, Silke; Wong, Ian C. K.; Standing, Joseph F.

doi:10.1111/pan.14425

Cited by 4 publications

(5 citation statements)

References 63 publications

(137 reference statements)

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“…These profiles ( Figure 5 ) described intravenous and intranasal dosing regimens. These indicated that morphine exposure in children after intranasal diamorphine 0.1 mg/kg was similar to after intranasal diamorphine 5 mg in adults [ 120 ].…”

Section: Practical Applicationsmentioning

confidence: 99%

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice

Morse

Cortínez

Anderson

2022

JCM

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The use of pharmacokinetic-pharmacodynamic models has improved anaesthesia practice in children through a better understanding of dose-concentration-response relationships, developmental pharmacokinetic changes, quantification of drug interactions and insights into how covariates (e.g., age, size, organ dysfunction, pharmacogenomics) impact drug prescription. Simulation using information from these models has enabled the prediction and learning of beneficial and adverse effects and decision-making around clinical scenarios. Covariate information, including the use of allometric size scaling, age and consideration of fat mass, has reduced population parameter variability. The target concentration approach has rationalised dose calculation. Paediatric pharmacokinetic-pharmacodynamic insights have led to better drug delivery systems for total intravenous anaesthesia and an expectation about drug offset when delivery is stopped. Understanding concentration-dependent adverse effects have tempered dose regimens. Quantification of drug interactions has improved the understanding of the effects of drug combinations. Repurposed drugs (e.g., antiviral drugs used for COVID-19) within the community can have important effects on drugs used in paediatric anaesthesia, and the use of simulation educates about these drug vagaries.

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Section: Practical Applicationsmentioning

confidence: 99%

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice

Morse

Cortínez

Anderson

2022

JCM

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“…Drug PK parameters can then be simulated to determine optimal dosing regimens for specific populations. [6][7][8][9] A major barrier to designing PKPD studies in children is the lack of PD scoring systems to help delineate the target effect. In this review we will discuss PKPD modeling in analgo-sedation, with a particular focus on PD endpoints and the difficulties associated with these measures in children.…”

Section: Introductionmentioning

confidence: 99%

“…In order to develop these models, the target‐concentration effect relationship needs to be well‐defined in order to determine a target concentration associated with a target effect. Drug PK parameters can then be simulated to determine optimal dosing regimens for specific populations 6–9 …”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children

Bardol

Pan

Walker

et al. 2023

Pediatric Anesthesia

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Pharmacokinetic pharmacodynamic modeling is an important tool which uses statistical methodology to provide a better understanding of the relationship between concentration and effect of drugs such as analgesics and sedatives. Pharmacokinetic pharmacodynamic models also describe between‐subject variability that allows identification of subgroups and dose adjustment for optimal pain management in individual patients. This approach is particularly useful in the pediatric population, where most drugs have received limited evaluation and dosing is extrapolated from adult practice. In children, the covariates of weight and age are used to describe size‐ and maturation‐related changes in pharmacokinetics. It is important to consider both size and maturation in order to develop an accurate model and determine the optimal dose for different age groups. An adequate assessment of analgesic and sedative effect using pain scales or brain activity measures is essential to build reliable pharmacokinetic pharmacodynamic models. This is often challenging in children due to the multidimensional nature of pain and the limited sensitivity and specificity of some measurement tools. This review provides a summary of the pharmacokinetic and pharmacodynamic methodology used to describe the dose–concentration–effect relationship of analgesics and sedation in children, with a focus on the different pharmacodynamic endpoints and the challenges of pharmacodynamic modeling.

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“…The aim of this study was to measure total plasma concentrations in infants undergoing lower abdominal surgery and combine this with data from other levobupivacaine studies to generate a neuraxial pharmacokinetic model which could then be used to predict levobupivacaine plasma concentrations at variable intervals after the initial caudal in neonates infants and older children. 5,6 2 | ME THODS…”

Section: Introductionmentioning

confidence: 99%

Levobupivacaine plasma concentrations following repeat caudal anesthetics

Frawley

Cortínez

Anderson

et al. 2022

Pediatric Anesthesia

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Aim: A single caudal anesthetic at the start of lower abdominal surgery is unlikely to provide prolonged analgesia. A second caudal at the end of the procedure extends the analgesia duration but total plasma concentrations may be associated with toxicity. Our aim was to measure total plasma levobupivacaine concentrations after repeat caudal anesthesia in infants and to generate a pharmacokinetic model for prediction of plasma concentrations after repeat caudal anesthesia in neonates, infants and children. Methods: Infants undergoing definitive repair of anorectal malformations orHirschsprung's disease received a second caudal anesthesia at the end of the procedure. Total levobupivacaine concentrations were assayed 3-4 times in the first 6 h after the initial caudal. These data were pooled with data from four studies describing plasma concentrations after levobupivacaine caudal or spinal anesthesia. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects models.Covariates included postmenstrual age and body weight. Parameter estimates were used to simulate concentrations after a repeat levobupivacaine 2.5 mg kg −1 caudal at 3 or 4 h following an initial levobupivacaine 2.5 mg kg −1 caudal.Results: Twenty-one infants (postnatal age 11-32 weeks, gestation 37-39 weeks, weight 5.2-8.6 kg) were included. The measured peak plasma concentration after repeat caudal levobupivacaine 2.5 mg kg −1 4 h after initial caudal was 1.38 mg L −1 (95% prediction interval 0.60-2.6 mg L −1 ) and 3 h after initial caudal was 1.46 mg L −1 (0.60-2.80) mg L −1 . Simulation of total plasma concentrations in neonates (7 kg, 57 weeks postmenstrual age) given caudal levobupivacaine 4 h after the initial caudal were 1.76 mg L −1 (0.68-3.50) mg L −1 if 2.5 mg kg −1 levobupivacaine was used and 0.88 mg L −1 (0.34-1.73) mg L −1 if 1.25 mg kg −1 of 0.125% levobupivacaine was used. In simulated older children (20 kg, 6 years), the mean maximum concentration was 1.43 mg L −1 (0.60-2.70) mg L −1 if 2.5 mg kg −1 levobupivacaine was repeated at 3 h. Conclusion:Repeat caudal levobupivacaine 2.5 mg kg −1 at 3 h after an initial 2.5 mg kg −1 dose does not exceed the concentration associated with systemic local anesthetic toxicity. In 2.5% of simulated neonates (weight 3.8 kg, PMA 40 weeks), repeat caudal

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Pharmacokinetic modeling and simulation to understand diamorphine dose‐response in neonates, children, and adolescents

Cited by 4 publications

References 63 publications

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice

Pharmacokinetic Pharmacodynamic Modelling Contributions to Improve Paediatric Anaesthesia Practice

Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children

Levobupivacaine plasma concentrations following repeat caudal anesthetics

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