Pharmacokinetics and Pharmacodynamics of Ionis-FXIRx, an Antisense Inhibitor of Factor XI, in Patients with End-Stage Renal Disease on Hemodialysis
Notice bibliographique
Résumé
Abstract BACKGROUND Patients with end-stage renal disease (ESRD) on hemodialysis are at high risk of both thrombotic and bleeding events. Experimental and clinical data indicate that reducing factor XI (FXI), a key component of the intrinsic pathway, prevents thrombosis without causing bleeding. FXI activity can be lowered with IONIS-FXIRx, a 2nd generation antisense oligonucleotide that specifically reduces human FXI mRNA expression in the liver. This study sought to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-FXIRx in participants with ESRD. METHODS In this Phase 2 multicenter study, we enrolled a total of 49 ESRD patients: (A) 6 participants receiving chronic in-center hemodialysis (HD) to receive an open-label single-dose of 300 mg IONIS-FXIRx either 5 minutes before or 10 minutes after HD and assessed the effects of HD on peak (Cmax) and the extent of exposure (AUC0-24hr) parameters of IONIS-FXIRx and (B) another 43 participants in a double-blind design to one of two multiple-dose regimens (200 mg or 300 mg) IONIS-FXIRx or placebo for 12 weeks with 12 weeks of additional follow up. In the double-blind portion, IONIS-FXIRx was administered subcutaneously ~10 minutes after HD. For PK, plasma trough concentration and apparent elimination half-life (t1/2λz) were evaluated. The PD parameters including FXI activity and antigen, aPTT, prothrombin time (PT), and INR were evaluated in the per-protocol population (N= 34) that was defined as all participants who received the complete protocol-specified administration of IONIS-FXIRx or placebo through week 8 and who did not have any major protocol violations. The rate and frequency of clotting on the HD filters and circuit were qualitatively measured with a clotting scale as an exploratory PD analysis. RESULTS The PK cohort included 6 males (5 white) with a mean age of 61 years. The plasma PK profile of IONIS-FXIRx was not significantly altered whether injected before or after HD. After multiple dosing, plasma Cmax values were dose-dependent and similar between Day 1 (first dose) and Day 78 (last dose), suggesting no accumulation of IONIS-FXIRx in ESRD participants after 12-weeks of dosing. After treatment cessation, IONIS-FXIRx had an apparent elimination half-life of approximately 2 weeks. In the double-blind portion of the study, 22 (51.2%) of the participants were male, 24 (55.8%) were white and the mean age was 59 years. Attenuation of FXI activity was associated with a reduction in the incidence of severe clotting events on both the air filter and dialyzer (Table). The reduction in severe clotting events was observed when FXI activity was CONCLUSIONS This study demonstrated that (i) HD had no effect on IONIS-FXIRx PK, (ii) IONIS-FXIRx was well tolerated and produced sustained, and dose-dependent reductions in FXI antigen and activity, and (iii) IONIS-FXIRx reduced severe dialysis circuit clotting events beyond standard heparin use. Collectively, these data support further evaluation of IONIS-FXIRx as a potentially safe, effective antithrombotic therapy in ESRD patients on HD. Download : Download high-res image (269KB) Download : Download full-size image Table 1 . Disclosures Bethune: Ionis Pharmaceuticals: Employment. Walsh: Population Health Research Institute: Employment; Ionis Pharmaceuticals: Consultancy. Jung: Ionis Pharmaceuticals: Employment. Yu: Ionis Pharmaceuticals: Employment. Geary: Ionis Pharmaceuticals: Employment. Bhanot: Ionis Pharmaceuticals: Employment.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».