Physiologically Based Pharmacokinetic Modeling of Metformin in Children and Adolescents With Obesity
Why this work is in the frame
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Bibliographic record
Abstract
Childhood obesity continues to rise in the United States and, with it, the off-label use of metformin for weight loss. The influence of age and obesity on the drug's disposition and exposure has not previously been studied using a mechanistic framework. Here, an adult physiologically based pharmacokinetic (PBPK) model of metformin was scaled to pediatric populations without obesity, with overweight/obesity, and with severe obesity; a published virtual population of children and adolescents with obesity was leveraged during model evaluation. When the pediatric model was simulated in groups aged 10 to 18 years, oral clearance following 1000 mg of metformin was higher (≈1200 mL/min) in those with obesity and severe obesity compared to the groups without and with overweight (≈1000 mL/min). In addition, simulated area under the concentration-time curve in older children and adolescents with obesity and severe obesity was comparable to that in adults with a similar dose-exposure relationship. Overall, simulations using the pediatric PBPK model support the use of adult doses of metformin in older children and adolescents with obesity. Moreover, the virtual population of children and adolescents with obesity offers a valuable tool to facilitate development of pediatric PBPK models for studying populations with obesity and, in turn, contribute information to inform drug labeling in this special population.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it