Step-up dosing of T-cell engaging bispecific antibodies
Step-up dosing starts with a small dose and increases it over the first cycle to the target dose, to lower the first concentration peak. A lower peak does not by itself tell how much cytokine release syndrome is reduced.
Definition
Step-up dosing (also called priming or ramp-up dosing) starts treatment with a low dose and increases it in steps, usually within the first cycle, until the target (maintenance) dose is reached. It is used for T-cell engaging bispecific antibodies, for which a high first dose can cause cytokine release syndrome (CRS).
Example
In the US intravenous product of mosunetuzumab, 1, 2 and 60 mg are given on Cycle 1 Days 1, 8 and 15, 60 mg on Cycle 2 Day 1, and 30 mg every 21 days from Cycle 3.
What PK can say
A smaller initial dose lowers the first concentration peak, and a population PK model can quantify how the first dose, the second dose and the interval change exposure. But a lower blood concentration does not tell how much less CRS occurs: that needs a link from PK to receptor occupancy and from occupancy to CRS, and public information supports each step to a different degree.
On this site
The mosunetuzumab analysis reimplements the published model and separates these steps. The tarlatamab analysis asks how far matching average exposure alone can set a dosing interval. Both are research and learning analyses, not dosing proposals.
Frequently asked questions
Why is step-up dosing used for T-cell engagers?
A high first dose can cause strong cytokine release. Starting low and stepping up lowers the first concentration peak, which is intended to reduce the severity of cytokine release syndrome.
Can PK modeling predict how much CRS a modified step-up schedule would cause?
Not from PK alone. It can show how exposure changes, but predicting CRS incidence needs validated links from PK to receptor occupancy and from occupancy to CRS, which public information does not fully provide.