Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059

Wu, Jen-Hao; Pennesi, Edoardo; Bautista, Francisco; Garrett, May; Fukuhara, Kei; Brivio, Erica; Ammerlaan, Anneke C. J.; Locatelli, Franco; van der Sluis, Inge M.; Rossig, Claudia; Chen-Santel, Christiane; Bielorai, Bella; Petit, Arnaud; Starý, Jan; Díaz-de-Heredia, Cristina; Rives, Susana; O’Marcaigh, Aengus; Rizzari, Carmelo; Engstler, Gernot; Nysom, Karsten; Rubio-San-Simón, Alba; Bruno, Benedicte; Bertrand, Yves; Brethon, Benoît; Rialland, Fanny; Plat, Geneviève; Dirksen, Uta; Sramkova, Lucie; Zwaan, C. Michel; Huitema, Alwin D. R.

doi:10.1007/s40262-024-01386-z

Table 3 Result of final InO population PK model and parameter estimates

From: Population Pharmacokinetics of Inotuzumab Ozogamicin in Pediatric Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia: Results of Study ITCC-059

InO population PK model:
\({CL}_{1}: 0.130 L/h(1-0.767ALL){(LBM/52.7kg)}^{1.05}(1-0.132*RITUX)\)
\({V}_{1}: 6.49 L*{(LBM/52.7kg)}^{0.977}\)
\({CL}_{2}: 0.569 L/h(1-0.362ALL)*{(LBM/52.7kg)}^{0.687}\)
\({k}_{des\_NHL}: 0.0577 {h}^{-1}\)
\({k}_{des\_ALL}: 0.0577 {h}^{-1}(1-0.924ALL){(BLSTABL/0.352)}^{-0.0484}{(AGE/60y)}^{-0.296}\)
\(Q:0.0437 L/h\) \(V_2: 4.74 L\)
For all pediatric patients with R/R BCP-ALL, covariate ALL = 1 and RITUX = 0

Parameters	Definition	NONMEM results				SIR results
		Estimate	95% CI		Shrinkage%	95% CI
		Estimate	Lower	Upper		Lower	Upper
CL₁, L/h	Linear clearance	0.130	0.117	0.143	–	0.120	0.141
ALL effect^a on CL₁		−0.767	−0.793	−0.741	–	−0.793	−0.740
LBM effect on CL₁		1.05	0.891	1.21	–	0.901	1.20
Concomitant rituximab treatment effect^b on CL₁		−0.132	−0.204	-0.0605	–	−0.202	– 0.0582
V₁, L	Volume of distribution in central compartment	6.49	6.24	6.74	–	6.26	6.70
LBM effect on V₁		0.977	0.861	1.09	–	0.847	1.10
CL₂, L/h	Initial estimate of time-dependent clearance	0.569	0.380	0.758	–	0.456	0.721
ALL effect on CL₂		−0.362	−0.597	−0.127	–	−0.507	– 0.173
LBM effect on CL₂		0.687	0.320	1.05	–	0.453	0.929
k_des, L/h	Decay coefficient of the time-dependent clearance^a	0.0577	0.0342	0.0812	–	0.0390	0.0826
ALL effect on k_des		−0.924	− 0.956	− 0.892	–	– 0.949	−0.893
BLSTABL effect on k_des		−0.0484	– 0.0686	– 0.0282	–	– 0.0641	– 0.0336
Age effect on k_des		−0.296	− 0.474	− 0.118	–	– 0.413	– 0.189
Q, L/h	Intercompartment clearance	0.0437	0.0348	0.0526	–	0.0383	0.0493
V₂, L	Volume of distribution in peripheral compartment	4.74	2.62	6.86	–	3.97	5.49
CL₁, IIV^c (%)		40.0%	31.6%	46.9%	20.8%	35.8%	44.9%
V₁, IIV^c (%)		40.1%	34.9%	44.8%	16.6%	36.9%	43.0%
CL₂, IIV^c (%)		73.7%	53.8%	89.2%	24.5%	63.8%	84.3%
k_des, IIV^c (%)		59.7%	40.7%	73.9%	51.3%	53.3%	67.1%
CL₁ − V₁; correlations (%)		0.136; 84.7%	0.0939	0.178	–	0.111	0.166
CL₁ − CL₂; correlations (%)		0.194; 65.8%	0.125	0.263	–	0.151	0.241
V₁ - CL₂; correlations (%)		0.204; 69.0%	0.144	0.264	–	0.167	0.242
Adult NHL, proportional residual error^d		0.444	0.393	0.495	18.5%	0.429	0.458
Adult ALL, proportional residual error^d		0.612	0.546	0.678		0.595	0.630
Pediatric ALL, proportional residual error^d		0.452	0.338	0.566		0.418	0.486

ALL acute lymphoblastic leukemia, BLSTABL baseline absolute blast counts in peripheral blood, CI confidence interval, IIV interindividual variability, InO inotuzumab ozogamicin, LBM baseline lean body mass, NHL non-Hodgkin lymphoma, OFV objective function value, PK pharmacokinetic, RITUX rituximab combination therapy, R/R relapsed/refractory, SIR sampling importance resampling procedure
^aALL effect accounts for disease type (NHL/ALL) and/or different bioanalytical analysis methods
^bReference group of concomitant rituximab treatment was “with rituximab” in the adult study. In this study, the reference was “without rituximab”
^cIIV was reported as percent coefficient of variation (%CV)
^dSeparate residual errors were included in the model to account for variability between trials. Reported as standard deviation

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