Population Pharmacokinetic Analysis of Selumetinib and Its N-desmethyl Metabolite in Japanese and Non-Japanese Pediatric Patients with Neurofibromatosis Type 1 and Inoperable Plexiform Neurofibromas

Table 3

Parameter estimates for the final PopPK model.

Parameter		Final model		Bootstrap
	Estimate	RSE (%)	Shrinkage (%)	Median (2.5^th percentile and 97.5^th percentile)
Fixed effects
CL (L/h)	7.06	3.2	—	7.08 (6.57, 7.66)
V2 (L)	15.1	4.1	—	15.1 (13.5, 16.8)
Q (L/h)	4.28	4.8	—	4.27 (3.63, 5.25)
V3 (L)	32.7	8.6	—	32.5 (25.4, 41.8)
Ka (h^−1)	4.91	8.5	—	4.81 (3.34, 8.07)
D1 (h)	0.591	10.1	—	0.587 (0.443, 0.796)
F1 (fraction)	0.662	Fixed	—	0.662
ALAG (h)	0.316	6.4	—	0.314 (0.249, 0.374)
Fm (fraction)	0.0748	Fixed	—	0.0748
CLm (L/h)	6.42	3.1	—	6.41 (5.99, 6.95)
BSA on CL	1.03	10.7	—	1.03 (0.80, 1.24)
BSA on V2	1.61	9.1	—	1.61 (1.32, 2.06)
BSA on CLm	1.37	7.9	—	1.37 (1.19, 1.58)
Interindividual variability
IIV in CL (CV%)	22.6	11.8	14.0	22.0 (16.7, 27.9)
Correlation CL ∼ CLm (%)	74.1	13.7	—	74.4 (51.8, 90.8)
IIV in CLm (CV%)	23.8	11.7	14.3	23.1 (17.2, 28.5)
IIV in V3 (CV%)	45.8	17.5	35.1	44.9 (26.9, 58.7)
IIV in Ka (CV%)	170.4	12.4	25.3	166.9 (129.8, 202.4)
IIV in ALAG (CV%)	58.3	11.9	14.5	58.6 (39.2, 79.5)
Residual variability
Selumetinib (CV%)	48.3	3.2	9.3	48.0 (43.0, 53.4)
N-desmethyl selumetinib (CV%)	39.5	3.5	9.9	39.4 (34.8, 43.6)

ALAG, absorption lag time; BSA, body surface area; CL, selumetinib clearance of central compartment; CLm, N-desmethyl selumetinib clearance; CV, coefficient of variation; D1, time of zero-order absorption; F1, absolute bioavailability; Fm, fraction metabolized; IIV, interindividual variability; Ka, first-order absorption rate constant; PopPK, population pharmacokinetic; Q, selumetinib intercompartmental clearance; RSE, relative standard error; V2, selumetinib volume of distribution of central compartment; V3, selumetinib volume of distribution of peripheral compartment.