GS‐443902 concentrations in peripheral blood mononuclear cells and dried blood spots among pregnant and non‐pregnant women receiving remdesivir for COVID‐19 treatment
Bibliographic record
Abstract
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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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 | 0.002 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".