Accumulation Ratio

Accumulation ratio compares exposure once repeated dosing has reached its plateau with exposure after a single dose. For a drug eliminated by a first-order process it depends on only one thing: the dosing interval expressed in half-lives. Dosing exactly one half-life apart doubles exposure at plateau. Dosing every two half-lives gives about a third more, and dosing at a third of a half-life gives roughly fivefold. The ratio is bounded, because each dose is a smaller addition to a larger residue until input and elimination balance.

The weekly incretin analogues illustrate the arithmetic. Semaglutide has a terminal half-life of roughly a week and is given weekly, so the interval is about one half-life and exposure roughly doubles between the first injection and the plateau, which it reaches after four to five weeks. Tirzepatide, with a half-life of around five days on the same weekly schedule, accumulates rather less. Liraglutide, at about thirteen hours and given daily, is dosed at nearly two half-lives and barely accumulates at all.

The number matters because it separates two things that are easy to merge. How high the plateau sits is set by the accumulation ratio; how long it takes to get there is set by the half-life alone and is unchanged by dose size or interval.

The usual misreading is that accumulation means indefinite build-up. Under first-order elimination the plateau is guaranteed, and warnings about a peptide stacking up without limit describe zero-order behaviour that these compounds do not show. The other trap is comparing accumulation ratios computed on different metrics: trough concentrations accumulate most, peaks least, and a ratio quoted without saying which one it describes is not comparable to another.