Repeat-dose inhaled mRNA-IL-1Ra PK/PD — computational analysis (comp-036)¶
Verdict: YELLOW. Repeat dosing partially salvages comp-033's RED single-dose Cmax verdict, but the high-confidence GREEN bar (median 95% of the 0-72h flare window above 80% receptor occupancy AND p25 >= 50%) is NOT reached by any of three dosing regimens. The modality is viable but at the edge — wet-lab dose-finding is needed to confirm or pivot.
Methodology reframe (load-bearing)¶
comp-033 used plasma Cmax-vs-anakinra-1.5-µg/mL as the decision gate (single inhale gives 0.025 µg/mL = 2% of anakinra → RED). comp-036 reframes to receptor-occupancy fraction over the 0-72h gout flare window — the clinically-relevant metric for a competitive antagonist. IL-1Ra-IL-1R1 Kd ~1 nM (range 0.1-10 nM log-uniform; Arend 1990 JCI DOI 10.1172/JCI114622; Schreuder 1997 Nature crystal at 2.7 Å). Receptor occupancy = [IL-1Ra]_nM / ([IL-1Ra]_nM + Kd). 80%-occupancy plasma threshold: median 73 ng/mL [p05-p95: 9-553]. Single-dose Cmax 25 ng/mL is below median threshold; anakinra steady-state 1500 ng/mL is 21× above (operates at ~85-90% mean occupancy).
Regimen scan (smallest N achieving sustained occupancy bar)¶
| Regimen | Best median sustained-80%-window | p25 | Median mean-occ | GREEN? |
|---|---|---|---|---|
| QD x1-14 days | 0.00 | 0.00 | 0.66 | NO — trough drops <80% every interval |
| BID x4-28 doses (2-14d) | 0.50-0.56 | 0.00 | 0.73-0.74 | NO — median 50%, p25=0 |
| Loading 2x + QD x14 | 0.32 | 0.00 | 0.75 | NO |
BID is qualitatively superior. BID 4+ doses (2+ days every-12h) reaches ~50% of flare window above 80% occupancy at mean occupancy ~73-74%. QD never sustains 80% (24h troughs too low). Anakinra steady-state (~85-90% mean occupancy) remains unmatched. p25 stays at 0% across all regimens — driven by Kd-prior uncertainty (ρ = -0.69) and translation-efficiency uncertainty (ρ = +0.58).
Sensitivity drivers¶
Top 3 drivers of mean window occupancy: Kd_nM (ρ = -0.69), translation_eff_ng_per_µg (ρ = +0.58), dose_mg_mrna (ρ = +0.24). Kd is now the #1 driver — comp-036's introduction of receptor-occupancy framing surfaces this previously-implicit uncertainty.
Clinical handoff (YELLOW path)¶
Single critical wet-lab measurement: integrated translation-efficiency mass ratio in human alveolar epithelium for inhaled m1Psi-mRNA-LNP. The 1,000-50,000 ng/µg prior is the #2 dominant uncertainty; ferret or NHP single-dose inhaled-LNP study with BAL protein quantification would resolve. Second priority: modern SPR IL-1Ra-IL-1R1 Kd measurement at physiological conditions to tighten 0.1-10 nM prior to <2× span.
Clinical reframe¶
Repeat-dose inhaled mRNA-IL-1Ra is NOT a like-for-like anakinra replacement at the receptor-occupancy level. It IS a meaningfully-better-than-nothing option that could displace prednisone for gout patients tolerating sub-anakinra occupancy in exchange for no SC injections, no glucocorticoid burden (acute glucose/BP/mood/sleep; chronic bone/cataract/adrenal), and substantial cost edge vs canakinumab. Decision reframes from "match anakinra?" (no) to "partial-suppression × side-effect-advantage worth it vs prednisone?" (plausibly yes — needs wet-lab data).
Frozen analysis archived to ./etc/experiments/comp-036-repeat-dose-inhaled-mrna-il1ra-pkpd/wiki-archive.md¶
Cross-references¶
comp-036 reproducible analysis | comp-033 single-dose precursor → inhaled-mrna-il1ra-pulse-computational.md | chassis-pending-interventions.md §4 | gout-action-guide.md | nlrp3-inflammasome.md