Patient data handling
In both cohorts FIX activity was measured using the one-stage assay
(OSA) according to local protocol. Laboratory specifications of all
participating sites are shown in Supplementary Table 1. All FIX activity
levels measured during bleeding episodes or
surgeries18 were excluded from this analysis.
Since the OSA does not distinguish FIX activity from the respective FIX
concentrates (e.g. residual FIX activity levels from the previous FIX
dose or currently present FIX concentrate), it is required to correct
for previously administered factor concentrates. To do so, we performed
the following corrections in line with Diao et al.16and previously reported PK analyses with FIX
concentrates9,12,19,20:
\(\left(1\right)\ Residual\ decay\ correction=\left(Predose\ activity-baseline\right)*e^{-kt}\)
\(\left(2\right)\ Corrected\ FIX\ activity=Measured\ FIX\ activity-baseline-residual\ decay\ correction\)
\(\left(3\right)\ k=\frac{\ln\left(2\right)}{t_{1/2}}\);
in which k represents the elimination rate constant of the
previously used concentrate for rFIX-Fc (Alprolix®), rFIX (Benefix®) or
rIX-FP (Idelvion®) calculated for each age group (<6, ≥6-12,
≥12-18 and ≥18 years). For these calculations, we used typical
half-lives (t1/2) of each age group as reported by the
respective European Public Assessment Report
(EPAR)21–23. Other patient characteristics collected
were age, height, body weight, lean body weight (LBW) and fat free mass
(FFM). Occasions were defined as a visit with PK assessment, as
described in literature24.