Electronic Supplementary Material
Online Resource Fig. S1 Goodness-of-fit plots for the full dataset model. Black line is the unity
line in the 2 upper panels. Red solid line represents the linear regression line in the upper
panels and the LOESS smoother in the lower panels; DV is corrected FIX activity and unit is
IU/dL (%); PRED is the prediction by population pharmacokinetic parameter estimates and unit
is IU/dL; IPRED is the prediction by individual pharmacokinetic parameter estimates and unit is
IU/dL; CWRES is conditional weighted residual; TIME unit is hour. DV dependent variable, FIX
factor IX
1
Online Resource Table S1 Summary of rFIXFc population pharmacokinetic model derived
from the full dataset
Population estimate (95% CI)a
Parameter
BW 0.432
)
73
CL = Typical CL × (
Typical CL for a 73-kg patient (dL/h)
BW exponent on CL
2.21 (2.10, 2.32)
0.432 (0.251, 0.613)
BW
V1 = Typical V1 × ( 73 )0.517
Typical V1 for a 73-kg patient (dL)
BW exponent on V1
70.6 (66.3, 74.9)
0.517 (0.282, 0.752)
Q2 (dL/h)
1.63 (1.39, 1.87)
V2 (dL)
99.1 (84.6, 114)
Q3 (dL/h)
45.6 (35.6, 55.6)
V3 (dL)
40.7 (38.3, 43.1)
IIVb on CL, %
19.7 (16.6, 22.8)
IOVc on CL, %
17.8 (17.0, 18.7)
IIV on V1, %
21.7 (17.9, 25.6)
IOV on V1, %
13.8 (12.3, 15.3)
IIV on Q2, %
48.1 (38.5, 57.6)
IIV on V2, %
51.0 (40.6, 61.3)
Correlation between IIV on CL and V1, %
Proportional residual error, %
Additive residual error, IU/dL
a
60.7
14.8 (9.56, 20.1)
0.279 (0.112, 0.445)
95% CI: The lower and upper limits for 95% CI were calculated asymptotically using the
standard errors estimated by the covariance step in NONMEM
b
IIV calculated as √𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒× 100
c
IOV calculated as √𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 × 100
BW body weight, CI confidence interval, CL clearance, IIV inter-individual variability, IOV interoccasion variability, rFIXFc recombinant factor IX FC, RSE relative standard error, Q2 inter-
2
compartmental clearance of compartment 2, Q3 inter-compartmental clearance of compartment
3, V1 volume of compartment 1, V2 volume of compartment 2, V3 volume of compartment 3.
3
Online Resource Table S2 Comparison of pharmacokinetic parameters derived from
population pharmacokinetic post hoc analysis and conventional pharmacokinetic analysis for
phase III study
Parameter (units)
Population
pharmacokinetics post hoc
(n=123)
Geometric mean (95% CI)
Conventional
pharmacokinetics analysis
(n=22)a
Geometric mean (95% CI)
CL (mL/h/kg)
3.3 (3.2, 3.5)
3.2 (2.8, 3.6)
Vss (mL/kg)
280.8 (266.4, 296)
314.8 (277.8, 356.8)
Terminal half-life (h)
81.1 (76.5, 86.1)
82.1 (71.4, 94.5)
MRT (h)
84.1 (79.8, 88.6)
98.6 (88.2, 110.3)
a
Pharmacokinetic parameters derived from 22 patients with intensive sampling schedule in Arm
1 sequential pharmacokinetic subgroup [8]
CI confidence interval, CL clearance, MRT mean residual time, Vss volume of distribution at
steady state
4