Pharmacokinetics of Plasminogen, Human-Tvmh in Subjects with Plasminogen Deficiency Type 1
Bibliographic record
Abstract
Introduction: Plasminogen deficiency type 1 (PLGD-1) or hypoplasminogenemia is an ultra-rare disease characterized by a reduction of both plasminogen activity and antigen levels, resulting in accumulation of extra-vascular fibrin-rich lesions on mucosal surfaces. Plasminogen, human-tvmh (PLG) is a plasma derived human plasminogen concentrate indicated for the treatment of subjects with PLGD-1 and FDA-approved in 2021 in the US (Shapiro et al, 2023). It is a lyophilized formulation containing the native circulating form of plasminogen, Glu-plasminogen, reported to have a longer t1/2 (2.2 days) than Lys-plasminogen (0.8 days) in healthy subjects (Collen et al, 1975). The (PK) characteristics of PLG administered IV to adults and children with PLGD-1 were assessed in phase 1 and phase 2/3 studies. Dosing intervals were determined based on individual PK profiles with the aim to increase and maintain plasminogen activity trough levels by at least an absolute 10% above baseline. Here are reported the PK properties of single and repeated doses of PLG administered every 2 to 4 days for 12 weeks in subjects with PLGD-1. Methods: A total of 15 subjects (9 adult and 6 pediatric subjects; 4 males and 11 females, 4 to 42 years of age) were administered 6.6 mg/kg PLG every 2 to 4 days for at least 48 weeks. Plasma samples were collected up to 96 hours post-dose after the first dose on week 1 and repeated doses on week 12 to obtain full PK profiles. Six subjects had their first dose in phase 1 and 9 subjects in the phase 2/3 study (segment 1). Samples were also collected every 2 weeks before PLG infusion to measure trough levels (phase 2/3 segment 2). Both plasminogen activity and antigen levels were measured using validated methods and baseline-adjusted PK parameters were derived from concentration-time curves using non-compartmental analysis (NCA). Serum samples for anti-drug antibodies (ADA) analyses were collected prior the first dose and on Week 4, Week 8, Week 12, and every 12 weeks until end of study. Results: All subjects were included in the PK population and received an actual dose of 5.6-6.8 mg/kg PLG infused over 10 to 17 minutes. Plasminogen activity: Similar plasminogen activity profiles were observed in the adult and pediatric PK populations. Mean (± standard deviation [SD]) absolute plasminogen activity was 22.1 ± 12.9% before the first dose and reached a trough level of 51.0 ± 12.0% after 12 weeks of treatment (corresponding to a mean absolute increase of 29.9 ± 14.1%). Mean (± SD) PLG peak concentration (Cmax) increased from 95 ± 23.5% after the first dose to 125 ± 23.3% after 12 weeks of treatment. Mean (± SD) PLG terminal half-life (t1/2) was 34.0 ± 11.7 hours after the first dose and increased slightly to 39.2 ± 6.2 hours after 12 weeks. Individual plasminogen activity trough levels were successfully increased and maintained by at least an absolute 10% above baseline. Transient ADA were confirmed in 2 subjects during the 12 weeks of treatment however their presence did not alter subjects' plasminogen activity levels and associated PK parameters. Plasminogen antigen: Similar plasminogen antigen profiles were observed in the adult and pediatric PK populations. However, larger variability was observed in plasminogen antigen levels compared to plasminogen activity, which did not allow reliable interpretation of plasminogen antigen levels and associated PK parameters. Conclusion: PLG administered IV at a dose of 6.6 mg/kg every 2 to 4 days increased plasminogen activity to physiological levels with no safety concerns. Dosing interval based on each individual PK profile obtained after the first dose adequately maintained plasminogen activity trough levels by at least 10% above baseline during 12 weeks of treatment. Robust plasminogen activity data obtained during phase 1 and phase 2/3 studies were used for the development of a population PK model supporting prophylactic replacement therapy for PLGD-1 patients that was successfully integrated into the WAPPS-Hemo platform (Chelle et al, 2024). References: Collen et al, Thromb Res. 1975; 7(4):515-29. Shapiro et al, Haemophilia. 2023; 1-9 Chelle et al, Haemophilia. 2024; 1-10
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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 | 0.000 | 0.001 |
| 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) | 0.001 | 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".