GS‐443902 concentrations in peripheral blood mononuclear cells and dried blood spots among pregnant and non‐pregnant women receiving remdesivir for COVID‐19 treatment
Notice bibliographique
Résumé
2 Background: Activation of remdesivir (RDV) has typically been assessed by measuring concentrations of GS-443902 (active triphosphate) in peripheral blood mononuclear cells (PBMC). We previously showed concentrations of RDV, and its major plasma metabolites were similar between pregnant and non-pregnant women with COVID-19, while those of GS-443902 in PBMC were ~50% lower in pregnancy. Dried blood spots (DBS) provide a simpler alternative to PBMC collection and may serve as another surrogate measure of cellular drug activation, but pregnancy status and inflammation due to COVID-19 may impact these measures. Here, we evaluated factors that affect GS-443902 in DBS and PBMC and relationships between cell types in pregnant and non-pregnant women with COVID-19. Methods: IMPAACT 2032 (NCT04582266) was a Phase IV prospective, open label, non-randomized, opportunistic study of hospitalized pregnant and non-pregnant women receiving intravenous RDV as part of clinical care for COVID-19. DBS and PBMC were isolated pre-dose and/or 23-h post-dose on infusion Days 3, 4 and 5. GS-443902 concentrations in each cell type were quantified using LC–MS/MS methods from 2 × 7 mm punches (DBS) or cell pellets (PBMCs). Generalized linear mixed effects modelling (1) evaluated the effect of pregnancy and baseline covariates on log-transformed GS-443902 in DBS and PBMC using forward selection (p < 0.2) and backwards elimination (p < 0.1) after adjusting for infusion number and (2) assessed relationships between GS-443902 in DBS vs. PBMC. Results: About 76 dB and PBMC observations were available from 51 participants (25 pregnant, 26 non-pregnant). Median (interquartile range) GS-443902 concentrations in DBS were 1807 (1395, 2292) and 1633 (1267, 2412) fmol/punch and in PBMC were 2.96 (0.79, 6.89) and 5.15 (3.22, 8.77) μM for pregnant and non-pregnant participants, respectively. In DBS, GS-443902 concentrations were 19% lower (90% CI −33, −2.5%) during pregnancy, increases in SBP (per 10 mmHg) were associated with an 8.1% decrease (90% CI −11.4%, −4.7%) and increases in ALP (per 10 U/L) and platelet count (per 50x109 cells/L) were associated with a 1.4% (90% CI 0.3%, 1.8%) and 5.3% (90% CI 0.8%, 13.4%) increase, respectively. In PBMC, GS-443902 concentrations were 45% lower (90% CI −19.4%, −61.8%) in pregnant vs. non-pregnant participants with each additional infusion. Increases in ALP and ALT (per 10 U/L) were associated with a 4.2% decrease (90% CI −7.7%, −0.6%) and 11.4% decrease (90% CI −18.8%, −3.4%) in GS-443902 concentrations in PBMC, respectively. For DBS vs. PBMC comparisons, GS-443902 concentrations in PBMCs increased by 7.7% (90% CI 4.0%, 11.6%) for every 100 fmol/punch increase in DBS for non-pregnant women; however, in pregnant women, there was a 4.4% decrease (90% CI −7.9%, −0.8%) for GS-443902 in PBMC for every 100 fmol/punch increase in DBS. Conclusions: Cellular disposition of GS-443902 between DBS and PBMCs differed by pregnancy status and other clinical factors associated with COVID-19 disease severity. The mechanisms and clinical significance of these differences are unknown. Further investigation into how pregnancy and other disease-specific factors affect cellular concentrations is warranted.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 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 tête enseignante, 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 ».