Fixed (flat) dosing versus weight-based dosing
Fixed dosing gives every patient the same dose; weight-based dosing scales it by body weight (mg/kg). For antibodies the difference matters mainly at the ends of the weight distribution.
A flat dose (also called a fixed dose) is the same dose given to every patient regardless of body weight; a weight-based dose scales with body weight (mg/kg). For antibodies, the two differ mainly at the ends of the weight distribution.
Definition
- Weight-based dosing: the dose is proportional to body weight, for example 2 mg/kg.
- Fixed (flat) dosing: every patient receives the same dose, for example 200 mg, regardless of weight.
Many monoclonal antibodies moved from weight-based to fixed doses on the basis of population PK models that compared exposure. Near the middle of the weight distribution the two give almost the same exposure.
Where they differ
Exposure depends on weight through clearance and volume, but not in proportion to weight. Fixed dosing therefore gives lower exposure in heavy patients and higher exposure in light ones; weight-based dosing does the opposite relative to the trial-tested range.
In a simulation of published models for pembrolizumab and nivolumab on an adult body-weight distribution, the share of patients whose steady-state trough was below the lower limit exceeded 10% at about 150 kg and above for pembrolizumab 200 mg (13.3%) and at about 100 kg and above for nivolumab 240 mg. Weight-based dosing was worse on the light side in the first interval. These are comparisons of exposure, not of effect.
Try it
The exposure explorer looks up these numbers by body weight, and the article gives the methods and limits.
See also: Ctrough (trough concentration) and dosing interval notation (Q2W, Q3W, Q4W).
Frequently asked questions
Is there a weight threshold for flat dosing?
There is no clinical threshold. In a simulation of published models on an adult weight distribution, the share of patients whose trough fell below the lower limit of the trial-tested range exceeded 10% at about 150 kg and above for pembrolizumab 200 mg (13.3%) and at about 100 kg and above for nivolumab 240 mg. That is a comparison of exposure under assumptions, not a point at which efficacy is lost.
Does fixed dosing give the same exposure as weight-based dosing?
Near the middle of the weight distribution, almost. At the extremes they differ: in the simulation, trough exposure fell below the trial range more often in heavy patients with fixed doses and in light patients with weight-based doses.
Does lower exposure at a very high weight mean lower efficacy?
Not necessarily. Exposure–response relationships of anti-PD-1 antibodies are reported to be flat, so whether falling slightly below the lower limit matters clinically is outside what the exposure comparison shows.