DOP58 IdeaL: a multi-centre prospective infliximab dose to level pharmacokinetic study during induction in paediatric Crohn’s disease
Bibliographic record
Abstract
Infliximab (IFX) is an effective therapy for Crohn's disease (CD), but pharmacokinetic data during induction are sparse. The objective of this study was to model the pharmacokinetic (PK) and use individual clearance (CL) estimates to explore relationships between PK and clinical remission in children with CD receiving IFX induction. A prospective study was conducted at 3 Canadian Children IBD Network sites. Baseline data collected included simple endoscopic score (SES-CD) and weighted Paediatric CD Activity index (wPCDAI). IFX doses ranged 5 to 10 mg/kg. Up to 8 IFX levels per subject were collected: trough and peak at doses 2 and 3, trough prior dose 4, between doses 3 and 4, and trough prior to dose 5. Free antibody to IFX (ATI) levels measured at doses 3, 4, and 5. Faecal calprotectin (FCP), wPCDAI, CBC, albumin (ALB), ESR, and CRP samples were also collected at each dose. NONlinear Mixed Effects Modelling was used to develop a population PK model using standard model building approaches. Covariate factors had to be significant at p < 0.001 and clinically relevant (>20% change in CL) to be retained. Dose and frequency may be adjusted clinically or based on preceding trough levels. Thirty-five subjects, 18 males, were recruited and followed for up to 22 weeks over 5 doses. Median age was 12.3 years (IQR: 10.2–14.8). Median dose for Dose 1 was 6.0 mg/kg (IQR: 5.0–7.0) and increased to 7.0 mg/kg (IQR: 5.0–8.3) for Dose 5. Eighty per cent of patients did not follow the standard induction and maintenance regimen of 0, 2, 6, and 14 weeks. Dose 4 had the most variability in frequencies with the median of Q6W. IFX CL was marked varied between subjects and improved during follow-up. Median baseline CL was 0.31 (IQR: 0.24,0.40). During single covariate evaluations, the following factors were identified as potentially predictive of IFX CL: ALB (negative correlation) and FCP, CRP, SES-CD, wPCDAI, and ESR (positive correlation). On back elimination, only ALB and CRP were important predictors. CL had a nonlinear correlation with weight where CL/kg was higher in those weigh < 30 kg vs. those >30 kg (p = 0.005). Twenty-nine subjects (83%) went into complete remission (wPCDAI <12.5). IFX CL of ≤0.39 l/day was a good predictor of remission status determined by wtPCDAI at Dose 5 (AUC [95% CI] = 0.828[0.63–1.00], p = 0.013). ATI levels drawn at Doses 4 and 5 were all negative. IFX CL is variable and affected by factors including weight, ALB, disease activity and endoscopic severity. Under dosing is common in lower age bracket, due to higher drug CL/kg using current weight-based dosing. Paediatric IBD patients may benefit from precision medicine using PK model-based (dashboard) dose adjustments where individualised dosing can be calculated based on individual patient factors.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".