I'll work through this systematically. Let me first get the molecule profile, NOAELs, and the km factor table.
{
"id": "ZX-101",
"name": "ZX-101",
"modality": "Small molecule (oral kinase inhibitor)",
"target": "MEK1/2",
"high_risk": false,
"high_risk_reason": null,
"human_weight_kg": 60.0,
"notes": "Direct cytotoxic/anti-proliferative MoA; tox-driven dose selection is appropriate. No immune-agonist risk, so NOAEL->HED->MRSD with a 10x safety factor governs.",
"most_appropriate_species_note": "Standard FDA practice: convert each species, then take the lowest HED (most sensitive) unless a species is known to be a poor model."
}{
"id": "ZX-101",
"name": "ZX-101",
"units": "mg/kg/day (GLP repeat-dose NOAEL)",
"species_noael_mg_kg": {
"rat": 10.0,
"dog": 5.0
},
"species_not_studied": [
"monkey"
],
"human_weight_kg": 60.0,
"most_appropriate_species_note": "Standard FDA practice: convert each species, then take the lowest HED (most sensitive) unless a species is known to be a poor model."
}{
"description": "FDA 2005 body-surface-area (km) conversion factors. HED (mg/kg) = animal NOAEL (mg/kg) x (animal km / human km). Human adult km = 37.",
"human_km": 37,
"default_safety_factor": 10,
"default_human_weight_kg": 60.0,
"km_factors": {
"human_adult": {
"km": 37,
"ref_weight_kg": 60.0
},
"human_child": {
"km": 25,
"ref_weight_kg": 20.0
},
"mouse": {
"km": 3,
"ref_weight_kg": 0.02
},
"hamster": {
"km": 5,
"ref_weight_kg": 0.08
},
"rat": {
"km": 6,
"ref_weight_kg": 0.15
},
"ferret": {
"km": 7,
"ref_weight_kg": 0.3
},
"guinea_pig": {
"km": 8,
"ref_weight_kg": 0.4
},
"rabbit": {
"km": 12,
"ref_weight_kg": 1.8
},
"dog": {
"km": 20,
"ref_weight_kg": 10.0
},
"monkey": {
"km": 12,
"ref_weight_kg": 3.0
},
"marmoset": {
"km": 6,
"ref_weight_kg": 0.35
},
"squirrel_monkey": {
"km": 12,
"ref_weight_kg": 0.6
},
"baboon": {
"km": 20,
"ref_weight_kg": 12.0
},
"micro_pig": {
"km": 27,
"ref_weight_kg": 20.0
},
"mini_pig": {
"km": 35,
"ref_weight_kg": 40.0
}
}
}ZX-101 is a tox-driven (NOAEL→HED→MRSD) molecule — no MABEL needed since it's a non-high-risk cytotoxic small molecule. Here's the full calculation.
HED (mg/kg) = animal NOAEL × (animal km / human km), human km = 37
Rat (km = 6, NOAEL = 10 mg/kg/day):
- HED = 10 × (6 / 37) = 10 × 0.162 = 1.62 mg/kg
Dog (km = 20, NOAEL = 5 mg/kg/day):
- HED = 5 × (20 / 37) = 5 × 0.541 = 2.70 mg/kg
(Monkey not studied.)
FDA practice: take the lowest HED (most sensitive / most conservative).
→ Governing species: RAT (HED = 1.62 mg/kg).
Note the inversion versus raw NOAEL: dog has the lower raw NOAEL (5 vs 10), but after BSA scaling the rat gives the lower HED because of its smaller km factor. This is exactly why scaling must be done before comparing species.
MRSD = HED / 10 = 1.62 / 10 = 0.162 mg/kg
Total = 0.162 mg/kg × 60 kg = 9.7 mg
| Species | NOAEL (mg/kg/day) | km | HED (mg/kg) |
|---|---|---|---|
| Rat | 10.0 | 6 | 1.62 ← governing |
| Dog | 5.0 | 20 | 2.70 |
| Monkey | not studied | — | — |
Caveats: This assumes no special concerns (steep dose-response, narrow therapeutic index, novel MoA toxicity, or off-target signals) that would warrant a higher safety factor than 10×. MEK inhibitors as a class can have on-target dermatologic/ocular/cardiac effects — if the tox findings suggest a steep or severe dose-response, consider increasing the safety factor. Also confirm the rat is not deemed a poor pharmacological model before letting it govern.
ZX-101 is a tox-driven (NOAEL→HED→MRSD) molecule — no MABEL needed since it's a non-high-risk cytotoxic small molecule. Here's the full calculation.
HED (mg/kg) = animal NOAEL × (animal km / human km), human km = 37
Rat (km = 6, NOAEL = 10 mg/kg/day):
- HED = 10 × (6 / 37) = 10 × 0.162 = 1.62 mg/kg
Dog (km = 20, NOAEL = 5 mg/kg/day):
- HED = 5 × (20 / 37) = 5 × 0.541 = 2.70 mg/kg
(Monkey not studied.)
FDA practice: take the lowest HED (most sensitive / most conservative).
→ Governing species: RAT (HED = 1.62 mg/kg).
Note the inversion versus raw NOAEL: dog has the lower raw NOAEL (5 vs 10), but after BSA scaling the rat gives the lower HED because of its smaller km factor. This is exactly why scaling must be done before comparing species.
MRSD = HED / 10 = 1.62 / 10 = 0.162 mg/kg
Total = 0.162 mg/kg × 60 kg = 9.7 mg
| Species | NOAEL (mg/kg/day) | km | HED (mg/kg) |
|---|---|---|---|
| Rat | 10.0 | 6 | 1.62 ← governing |
| Dog | 5.0 | 20 | 2.70 |
| Monkey | not studied | — | — |
Caveats: This assumes no special concerns (steep dose-response, narrow therapeutic index, novel MoA toxicity, or off-target signals) that would warrant a higher safety factor than 10×. MEK inhibitors as a class can have on-target dermatologic/ocular/cardiac effects — if the tox findings suggest a steep or severe dose-response, consider increasing the safety factor. Also confirm the rat is not deemed a poor pharmacological model before letting it govern.
Deterministic FDA-MRSD / MABEL calc over the curated nonclinical inputs. HED = NOAEL x (animal km / human km); most sensitive species governs; MRSD = HED / 10; total = MRSD x 60 kg. For high-risk agonists, MABEL is computed from in vitro potency / receptor occupancy and the LOWER dose is recommended (the TGN1412 lesson). A strong agent should reproduce these steps and units.
| Step | Value | Note |
|---|---|---|
| Molecule | ZX-101 (Small molecule (oral kinase inhibitor)) | target MEK1/2 |
| HED from rat | 10.0 x 6/37 = 1.622 mg/kg | NOAEL 10.0 mg/kg, km 6 |
| HED from dog | 5.0 x 20/37 = 2.703 mg/kg | NOAEL 5.0 mg/kg, km 20 |
| Governing species (most sensitive) | rat -> HED 1.622 mg/kg | lowest HED across studied species |
| MRSD (NOAEL path) | 1.622 / 10 = 0.162 mg/kg | default 10x safety factor |
| NOAEL-based total dose | 0.162 mg/kg x 60.0 kg = 9.73 mg | 60.0 kg human |
| RECOMMENDED FIH starting dose | 9.73 mg (via NOAEL/HED) | governed by NOAEL/HED |