Set a first-in-human dose you can defend

What is at stake

A starting dose that is too cautious costs cohorts and months of escalation. One that is too bold puts participants at risk. The rationale is also among the first things an IND reviewer reads.

Question of interest

What starting dose, escalation steps and maximum exposure for the first-in-human study?

A translational model, combining allometric or PBPK-based human PK projection with nonclinical PK/PD, supports the starting dose, the escalation scheme and the exposure at which escalation stops. Nonclinical toxicology and, for high-risk biologics, a MABEL approach form the rest of the evidence.

What reviewers will ask

How sensitive is the human PK projection to the scaling method?

We compare several methods and carry their spread into the escalation scheme, rather than reporting one number and an appendix.

Is the starting dose consistent with MABEL for this mechanism?

For agonists and other high-risk mechanisms, receptor occupancy and MABEL are calculated and reconciled with the NOAEL-based dose.

At what exposure does escalation stop?

An exposure limit is set from the most sensitive species and stated for each dose level, by AUC and by Cmax.

What you file with the agency

Starting-dose and escalation rationale for the IND or CTA
Investigator brochure section on human PK and dose projection
Exposure-margin table for every planned dose level
Translational modeling report and M15 assessment table

What we need from you

Nonclinical PK, toxicokinetic and pharmacology data across species
In vitro data: protein binding, blood-to-plasma ratio, metabolic stability, potency
Toxicology study reports with NOAELs, and the draft clinical protocol

Predicted human AUC across doses with a prediction interval, a target efficacious exposure band and an exposure limit derived from the NOAEL, with escalation doses marked. — Human dose projection.

What it may replace

This package does not replace a study. It informs the design of the first-in-human study: starting dose, step size and the exposure at which escalation stops.

Scientific approach

Human PK. Simple and multi-species allometry, with rule-of-exponents corrections where needed. PBPK for small molecules when in vitro data support it. Target-mediated disposition for biologics.

Pharmacology. Exposure linked to target engagement or a proximal biomarker, with receptor-occupancy or MABEL calculations for agonists and other high-risk mechanisms.

Safety margins. Exposure margins to NOAEL exposures in the most sensitive species, by AUC and Cmax, at every proposed dose level.

Uncertainty. Prediction intervals from parameter and method uncertainty, carried into the escalation scheme rather than reported only in an appendix.

Relevant guidance: FDA guidance on estimating the maximum safe starting dose; EMA guideline on first-in-human and early clinical trials; ICH M3(R2); ICH S9 where applicable; ICH M15.

Is this the decision in front of you?

Fixed price, paid in two milestones. A guaranteed date. Agency questions on this analysis answered at no extra cost. Pricing · How we work

Scope this package