{
"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
}
}
}{
"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
}
}
}{
"id": "ZX-101",
"name": "ZX-101",
"pharmacology": null,
"note": "No MABEL pharmacology provided: this molecule is not an immunostimulatory/agonist high-risk biologic, so NOAEL/HED with the default safety factor governs."
}To recommend a first-in-human starting dose for ZX-101, an oral small-molecule MEK1/2 inhibitor, let's calculate the Human Equivalent Dose (HED) using the GLP tox NOAELs for rat and dog species, along with body-surface-area scaling.
The formula to calculate the HED is:
[
\text{HED} (\text{mg/kg}) = \text{animal NOAEL} (\text{mg/kg}) \times \left(\frac{\text{animal km}}{\text{human km}}\right)
]
[
\text{HED}_{\text{rat}} = 10 \times \left(\frac{6}{37}\right) \approx 1.62 \, \text{mg/kg}
]
[
\text{HED}_{\text{dog}} = 5 \times \left(\frac{20}{37}\right) \approx 2.70 \, \text{mg/kg}
]
The governing species is the one with the lowest HED, which in this case is the rat (1.62 mg/kg).
The MRSD is calculated with a safety factor of 10 and is based on the governing HED:
[
\text{MRSD} = \text{HED}_{\text{governing species}} \times \text{safety factor} = 1.62 \, \text{mg/kg} \times 10 = 16.2 \, \text{mg/kg}
]
[
\text{Total Dose} = 16.2 \, \text{mg/kg} \times 60 \, \text{kg} = 972 \, \text{mg}
]
Therefore, the recommended first-in-human starting dose for ZX-101 is 972 mg.
To recommend a first-in-human starting dose for ZX-101, an oral small-molecule MEK1/2 inhibitor, let's calculate the Human Equivalent Dose (HED) using the GLP tox NOAELs for rat and dog species, along with body-surface-area scaling.
The formula to calculate the HED is:
[
\text{HED} (\text{mg/kg}) = \text{animal NOAEL} (\text{mg/kg}) \times \left(\frac{\text{animal km}}{\text{human km}}\right)
]
[
\text{HED}_{\text{rat}} = 10 \times \left(\frac{6}{37}\right) \approx 1.62 \, \text{mg/kg}
]
[
\text{HED}_{\text{dog}} = 5 \times \left(\frac{20}{37}\right) \approx 2.70 \, \text{mg/kg}
]
The governing species is the one with the lowest HED, which in this case is the rat (1.62 mg/kg).
The MRSD is calculated with a safety factor of 10 and is based on the governing HED:
[
\text{MRSD} = \text{HED}_{\text{governing species}} \times \text{safety factor} = 1.62 \, \text{mg/kg} \times 10 = 16.2 \, \text{mg/kg}
]
[
\text{Total Dose} = 16.2 \, \text{mg/kg} \times 60 \, \text{kg} = 972 \, \text{mg}
]
Therefore, the recommended first-in-human starting dose for ZX-101 is 972 mg.
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 |