Perfect! Now I'll calculate the HED for each species and determine the first-in-human starting dose.

ZX-101 First-in-Human Starting Dose Recommendation

GLP Repeat-Dose NOAELs

• Rat: 10.0 mg/kg/day
• Dog: 5.0 mg/kg/day
• Monkey: Not studied

HED Calculations (FDA BSA Method)

Using the formula: HED (mg/kg) = Animal NOAEL (mg/kg) × (Animal km / Human km)

Human km = 37

Governing Species & MRSD

Rat is the most sensitive species with an HED of 1.62 mg/kg.

Maximum Recommended Starting Dose (MRSD):
- NOAEL HED: 1.62 mg/kg
- Safety factor: 10×
- MRSD = 1.62 ÷ 10 = 0.162 mg/kg

Total Dose at 60 kg Body Weight

First-in-Human Starting Dose = 0.162 mg/kg × 60 kg = 9.72 mg

Recommendation: Start at ~10 mg (or 9.7 mg) as a single oral dose for the first cohort.

Summary

• Governing species: Rat (lowest HED)
• Critical HED: 1.62 mg/kg
• MRSD: 0.162 mg/kg
• Starting dose at 60 kg: ~10 mg

This represents a 10-fold safety margin from the most sensitive animal model, consistent with FDA guidance for conventional small-molecule kinase inhibitors with cytotoxic activity.

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.

Step 1 — HED per species

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.)

Step 2 — Governing species

FDA practice: take the lowest HED (most sensitive / most conservative).

• Rat HED = 1.62 mg/kg ← lowest
• Dog HED = 2.70 mg/kg

→ 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.

Step 3 — MRSD (apply 10× safety factor)

MRSD = HED / 10 = 1.62 / 10 = 0.162 mg/kg

Step 4 — Total dose at 60 kg

Total = 0.162 mg/kg × 60 kg = 9.7 mg

Summary

• Governing species: Rat (lowest HED, most conservative)
• HED: 1.62 mg/kg
• Safety factor: 10×
• MRSD: 0.16 mg/kg
• Recommended FIH starting dose at 60 kg: ≈ 9.7 mg (round to ~9–10 mg)

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.

Step 1 — GLP Repeat‑Dose NOAELs

• Rat: 10 mg/kg/day
• Dog: 5 mg/kg/day

Human Km = 37 (60‑kg adult)
HED formula (FDA 2005):

[
\textbf{HED (mg/kg)} = \text{Animal NOAEL (mg/kg)} \times \left(\frac{K_m\text{ animal}}{37}\right)
]

Step 2 — Convert to Human Equivalent Dose (HED)

Rat

Km (rat) = 6

[
10 \times \frac{6}{37} = 1.62 \text{ mg/kg}
]

Dog

Km (dog) = 20

[
5 \times \frac{20}{37} = 2.70 \text{ mg/kg}
]

Step 3 — Governing Species

Lowest HED = 1.62 mg/kg (rat)

→ Rat is the governing species

Step 4 — Apply FDA Default Safety Factor (10×)

[
\textbf{MRSD (mg/kg)} = \frac{1.62}{10} = 0.162 \text{ mg/kg}
]

Step 5 — Convert to Total Daily Dose (60‑kg Human)

[
0.162 \times 60 = 9.7 \text{ mg}
]

✅ Recommended First‑in‑Human Starting Dose

📌 Final Recommendation

Proposed FIH starting dose: 10 mg orally once daily

This is:
- Based on the most sensitive species (rat)
- Derived via FDA BSA scaling
- Includes the standard 10× safety factor
- Appropriate for a small‑molecule oncology MEK inhibitor where NOAEL‑based MRSD is standard

If you'd like, I can also project exposure margins versus expected efficacious exposure to sanity‑check whether this is likely to be pharmacologically active or strictly sub‑therapeutic.

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.

NOAEL Values:

• Rat NOAEL: 10 mg/kg
• Dog NOAEL: 5 mg/kg

km Factors:

• Rat km: 6
• Dog km: 20
• Human km: 37

HED Calculation

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)
]

For Rat:

[
\text{HED}_{\text{rat}} = 10 \times \left(\frac{6}{37}\right) \approx 1.62 \, \text{mg/kg}
]

For Dog:

[
\text{HED}_{\text{dog}} = 5 \times \left(\frac{20}{37}\right) \approx 2.70 \, \text{mg/kg}
]

Governing Species:

The governing species is the one with the lowest HED, which in this case is the rat (1.62 mg/kg).

Maximum Recommended Starting Dose (MRSD):

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}
]

Total Dose Calculation for 60 kg Adult:

[
\text{Total Dose} = 16.2 \, \text{mg/kg} \times 60 \, \text{kg} = 972 \, \text{mg}
]

Summary of the Recommended First-in-Human Starting Dose:

• HED (Rat): 1.62 mg/kg
• HED (Dog): 2.70 mg/kg
• Governing Species: Rat
• MRSD: 16.2 mg/kg
• Total Dose for 60 kg Human: 972 mg

Therefore, the recommended first-in-human starting dose for ZX-101 is 972 mg.