If I want to achieve a higher trough FVIII level, which is better — increasing the dose or the frequency?¶
Answer: Increasing the frequency is more efficient than increasing the dose.
PK rationale: trough depends on the ratio of dosing interval to half-life. For a short-half-life protein, doubling the dose adds only about one extra half-life of coverage near the end of the interval, whereas shortening the interval compounds far better.
- Collins et al. quantified this: to hold a trough of 1–1.5 IU/dL in a 70-kg adult (median t½ 10.4 h), the dose per infusion needed was 120 IU daily vs 700 IU every other day vs 3570 IU every third day — a ~30-fold swing in per-infusion dose. Stretching the interval demands exponentially more factor to hold the same trough.
- Crossover PK study (Hua et al., daily 5 IU/kg vs every-other-day 10 IU/kg — equal total factor): at steady state the daily regimen produced double the trough (6% vs 3%) (Haemophilia 2017).
- rFVIIIFc simulation (Berntorp et al.): a longer half-life relaxes the trade-off. rFVIIIFc's lower clearance gave higher troughs and fewer days below threshold at similar or reduced factor use — e.g. at the same 3×30 IU/kg, the first-week trough was ~7.8 vs 2.7 IU/dL for rFVIIIFc vs conventional rFVIII (Haemophilia 2016).