Pharmacokinetics of anti tumor necrosis factor antibody (infliximab) in children with acute GVHD involving the gastrointestinal tract
Bibliographic record
Abstract
Infliximab (REMICADE®, Centocor), a chimeric anti-TNFα monoclonal antibody, has been used in the management of patients with steroid-refractory acute GVHD. Though preliminary results using infliximab have been encouraging, the pharmacokinetics (Pk) of infliximab in this clinical setting have yet to be defined. A prospective trial examining the Pk of infliximab in pediatric patients with gastrointestinal (GI) GVHD was undertaken. Five subjects (median 11 yrs, range 9 mo–17 yrs) with GI GVHD were enrolled. All subjects had histologic confirmation of GVHD and had failed > 48 hours of corticosteroids prior to study entry. Subjects received a single 5 mg/kg dose of infliximab. PK and pharmacodynamic samples were drawn at 16 time points (hours 0, 1, 2, 6, 24, 48, 96, weekly days 7–42, days 56, 70, 84). Based upon existing Pk data in patients with Crohn’s disease, the time required to reach a trough concentration ≤2 mcg/ml was the defined primary study endpoint. Results: Dosing was well tolerated in all five subjects. Infliximab concentrations are as follows: Peak concentrations (Cmax) ranged from 64-160 mcg/ml and were achieved by hours 2–6. Drug concentrations > 20 mcg/ml were maintained for > 7 days in all subjects. The primary endpoint (trough concentration □ 2 mcg/ml) was reached on days 28, 35, 21, 35, and 7(asterisk) (median 28 days, mean 25 days), respectively. Infectious complications with a possible attribution to infliximab included endocarditis on day 21 in 1 subject and CMV reactivation 1 month post infliximab in a second subject. No invasive fungal infections were seen. Durable complete responses of GVHD were seen in 2 subjects by days 7 and 28, respectively. Two subjects are alive (6 months and 16 months). Conclusion: In summary, pharmacokinetics of infliximab indicate that concentrations > the targeted threshold level can be maintained for several weeks following a single 5 mg/kg dose in patients with GI GVHD. A phase II clinical trial, with dosing intervals based upon these Pk parameters, will be required. This investigator-initiated study was conducted through the Pediatric Blood and Marrow Transplant Consortium. Infliximab and partial financial support were provided by Centocor, Inc. Infliximab (REMICADE®, Centocor), a chimeric anti-TNFα monoclonal antibody, has been used in the management of patients with steroid-refractory acute GVHD. Though preliminary results using infliximab have been encouraging, the pharmacokinetics (Pk) of infliximab in this clinical setting have yet to be defined. A prospective trial examining the Pk of infliximab in pediatric patients with gastrointestinal (GI) GVHD was undertaken. Five subjects (median 11 yrs, range 9 mo–17 yrs) with GI GVHD were enrolled. All subjects had histologic confirmation of GVHD and had failed > 48 hours of corticosteroids prior to study entry. Subjects received a single 5 mg/kg dose of infliximab. PK and pharmacodynamic samples were drawn at 16 time points (hours 0, 1, 2, 6, 24, 48, 96, weekly days 7–42, days 56, 70, 84). Based upon existing Pk data in patients with Crohn’s disease, the time required to reach a trough concentration ≤2 mcg/ml was the defined primary study endpoint. Results: Dosing was well tolerated in all five subjects. Infliximab concentrations are as follows: Peak concentrations (Cmax) ranged from 64-160 mcg/ml and were achieved by hours 2–6. Drug concentrations > 20 mcg/ml were maintained for > 7 days in all subjects. The primary endpoint (trough concentration □ 2 mcg/ml) was reached on days 28, 35, 21, 35, and 7(asterisk) (median 28 days, mean 25 days), respectively. Infectious complications with a possible attribution to infliximab included endocarditis on day 21 in 1 subject and CMV reactivation 1 month post infliximab in a second subject. No invasive fungal infections were seen. Durable complete responses of GVHD were seen in 2 subjects by days 7 and 28, respectively. Two subjects are alive (6 months and 16 months). Conclusion: In summary, pharmacokinetics of infliximab indicate that concentrations > the targeted threshold level can be maintained for several weeks following a single 5 mg/kg dose in patients with GI GVHD. A phase II clinical trial, with dosing intervals based upon these Pk parameters, will be required. This investigator-initiated study was conducted through the Pediatric Blood and Marrow Transplant Consortium. Infliximab and partial financial support were provided by Centocor, Inc.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.000 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".