Are body surface area based estimates of liver volume applicable to children with overweight or obesity? An in vivo validation study

Hosey-Cojocari, Chelsea; Chan, Sherwin S; Friesen, Craig A.; Robinson, A.; Williams, Veronica; Swanson, Erica; O’Toole, Daniel; Radford, Jansynn; Mardis, Neil; Johnson, Trevor N.; Leeder, J. Steven; Shakhnovich, Valentina

doi:10.1111/cts.13059

Cited by 8 publications

(12 citation statements)

References 40 publications

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“…This finding concords with data from critically ill adult patients that have shown clearance to be proportional to estimated creatinine clearance 27 . No other studies have found an association between body surface area and clearance of desacetylcefotaxime, although a relationship between body surface area and liver volume has been recently identified in children 28 and this may account for the relationship identified for the metabolite in our study.…”

Section: Discussionsupporting

confidence: 44%

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

Valero

Dorofaeff

Coulthard

et al. 2022

Preprint

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Objectives: This study aimed to describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling. Methods: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve PK/PD targets, including 100% fT>MIC with an MIC breakpoint of 1 mg/L. Results: 36 patients (0.2 - 12 y) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L and 39.4 L/h, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg Q6h was only able to achieve the PK/PD target of 100% fT>MIC in patients > 10 kg and with impaired renal function or patients of 40 kg with normal renal function. Conclusions: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.

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Section: Discussionsupporting

confidence: 44%

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

Valero

Dorofaeff

Coulthard

et al. 2022

Preprint

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“…Though the previously published population PK model could not be validated for use with external datasets, the model was successfully refined using data from these sites, identifying weight as an additional model significant covariate. Weight represents an additional indicator of the child's maturation, as weight corresponds to organ growth and cardiac output 34,35 . The refined model can predict future concentrations with acceptable accuracy and bias when guided by as few as three concentrations.…”

Section: Discussionmentioning

confidence: 99%

External assessment and refinement of a population pharmacokinetic model to guide tacrolimus dosing in pediatric heart transplant

et al. 2023

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Heart transplantation is an accepted therapeutic option for children with end-stage heart failure, congenital heart disease, and cardiomyopathy. More than 400 heart transplants are performed annually in children across the United States with improving outcomes in recent decades, though mortality from rejection, infection, and coronary vasculopathy remains significant. 1,2 Transplant survival in excess of 20 years following heart transplantation has been observed, with more than 70% of transplants expected to achieve greater than 5year survival. 1,3 Much of this success can be attributed to the use of immunosuppressive therapy to prevent the rejection of the transplanted heart.The calcineurin inhibitors (CNI) tacrolimus and cyclosporine play a vital role in immunosuppressive therapy. Currently, tacrolimus is preferred in comparison to cyclosporine, due to its improved safety

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“…Further longitudinal research on larger populations will be necessary to confirm these observations and to determine whether the observed differences in growth trajectories are similar across pediatric centers. PBPK simulations of drug concentrations in children rely on scaling factors, such as liver volume, which can be estimated for children with normal weight, as well as obesity, as a function of body surface area, 2 , 3 which can be calculated with height and weight. Therefore, reliable estimates of height and weight may be critical to accurately estimating drug concentrations in the pediatric population of interest, 32 and the development of growth curves accurately reflecting the pediatric patient population of interest is an essential preliminary step in pediatric PBPK model development when growth trajectories for the population differ substantially from typical healthy peers (e.g., children with obesity and children who develop T2DM).…”

Section: Discussionmentioning

confidence: 99%

“…Some physiological processes, such as hepatic drug clearance, trend with patient size, and equations have been developed to provide estimates of corresponding anatomic features, such as liver volume, as a function of body size to assist with extrapolation of in vitro enzyme activity to in vivo clearance. 2 , 3 Because children continuously grow and develop during childhood, incorporation of growth curves into these PBPK models is critical for accurately simulating pharmacokinetics across the pediatric age range. Pediatric growth trajectories have been incorporated into PBPK models, but these are largely representative of healthy‐weight children and do not accurately capture the obesity epidemic of the 21st century.…”

Section: Introductionmentioning

confidence: 99%

“…PBPK models integrate physiological and anatomic information for the population of interest with physicochemical information for the drug. Some physiological processes, such as hepatic drug clearance, trend with patient size, and equations have been developed to provide estimates of corresponding anatomic features, such as liver volume, as a function of body size to assist with extrapolation of in vitro enzyme activity to in vivo clearance 2,3 . Because children continuously grow and develop during childhood, incorporation of growth curves into these PBPK models is critical for accurately simulating pharmacokinetics across the pediatric age range.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pediatric growth patterns in youth‐onset type 2 diabetes mellitus: Implications for physiologically‐based pharmacokinetic models

Hosey-Cojocari

Halpin

Shakhnovich

et al. 2022

Clinical Translational Sci

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An accurate understanding of the changes in height and weight of children with age is critical to the development of models predicting drug concentrations in children (i.e., physiologically‐based pharmacokinetic models). However, curves describing the growth of a typical population of children may not accurately characterize growth of children with various conditions, such as obesity. Therefore, to develop height and weight versus age growth curves for youth who were diagnosed with type 2 diabetes, we extracted data from electronic medical records. Robust nonlinear models were parameterized to the equations describing height and weight versus age as defined by the Centers for Disease Control and Prevention (CDC). CDC z‐scores were calculated using an internal program. The growth curves and z‐scores were compared to CDC norms. Youth with type 2 diabetes were increasingly heavier than CDC norms from early childhood. Except for a period around puberty, youth with type 2 diabetes were, on average, shorter than CDC norms, resulting in shorter average adult height. Deviations in growth were apparent in youth who develop type 2 diabetes; such deviations may be expected for other conditions as well, and disease‐specific growth curves should be considered during development of model‐informed drug development for pediatric conditions.

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Are body surface area based estimates of liver volume applicable to children with overweight or obesity? An in vivo validation study

Abstract: Are body surface area (BSA) based estimates of liver volume applicable to children with overweight or obesity? An in-vivo validation study

Cited by 8 publications

References 40 publications

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

External assessment and refinement of a population pharmacokinetic model to guide tacrolimus dosing in pediatric heart transplant

Pediatric growth patterns in youth‐onset type 2 diabetes mellitus: Implications for physiologically‐based pharmacokinetic models

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