Population pharmacokinetics of imatinib mesylate in healthy Korean subjects

Gab-jin Park; Wan-Su Park; Soohyun Bae; Sung-min Park; Seunghoon Han; Dong-Seok Yim

doi:10.12793/tcp.2016.24.2.96

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Park, Park, Bae, Park, Han, and Yim: Population pharmacokinetics of imatinib mesylate in healthy Korean subjects

Original Article

Translational and Clinical Pharmacology 2016;24(2):96-104.

Published online: 15 June 2016

DOI: https://doi.org/10.12793/tcp.2016.24.2.96

Population pharmacokinetics of imatinib mesylate in healthy Korean subjects

Gab-jin Park^1,², Wan-Su Park², Soohyun Bae², Sung-min Park², Seunghoon Han^1,², Dong-Seok Yim^1,^2,^∗

¹Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, Seoul 06591, Korea

²PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea

^∗Correspondence: D. S. Yim; Tel: +82-2-2258-7327, Fax: +82-2-2258-7876, E-mail: yimds@catholic.ac.kr

Received 18 May 2016 Revised 30 May 2016 Accepted 31 May 2016

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Imatinib (Gleevec^TM; Novartis Pharmaceuticals) is an orally administered protein-tyrosine kinase inhibitor. The goal of this study was to investigate the population pharmacokinetics (PK) of imatinib (as imatinib mesylate) in healthy male Koreans. A total of 1,773 plasma samples from 112 healthy male volunteers enrolled in three phase I clinical studies were used. Among the subjects, 76 received 400 mg and 36 received 100 mg as single oral doses. Peripheral blood sampling for PK analysis was done at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 60 and 72 (at 400 mg group) h after dosing. The first-order conditional estimation with interaction method of NONMEM® (ver. 7.3) was used to build the population PK model. A two-compartment model with Weibull absorption and elimination gave the best fit to the data. The estimates of clearance (CL/F), volume of central compartment (Vc/F), inter-compartmental clearance (Q/F), peripheral volume (Vp/F) and their interindividual variabily (%CV) were 13.6 L/h (23.4%), 153 L (29.2%), 8.64 L/h (35.9%) and 64 L (67%), respectively.

Keywords: Imatinib, population pharmacokinetics, NONMEM, Weibull

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Figure 1.

Pharmacokinetic model for imatinib.

Figure 2.

Scatterplots representing correlation between ETAs.

Figure 3.

Basic goodness-of-fit plot for the PK model. Open circles are observations. Solid lines are line of identity. Red lines are LOESS (locally weighted regression) smoothed lines.

Figure 4.

Visual predictive checks of the final PK model classified by dose of 100 mg and 400 mg.

Table 1.

Study-subjects demographic characteristics

Study	Subjects N (%)	Samples N (%)	Sampling points (h)	Age (years) mean (range)	Weight (kg) mean (range)	Dose N (%)
Study	Subjects N (%)	Samples N (%)	Sampling points (h)	Age (years) mean (range)	Weight (kg) mean (range)	100 mg	400 mg
1	38 (33.9)	606 (34.2)	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 72	25.21 (20–44)	66.17 (53.4–76.4)	–	38
2	38 (33.9)	593 (33.4)	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 72	27.11 (20–45)	66.79 (54–83.8)	–	38
3	36 (32.2)	574 (32.4)	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 60	24.33 (20–32)	68.49 (52.8–85.9)	36 (32.1)	–
Total	112 (100)	1773 (100)	–	25.57 (20–45)	67.12 (52.8–85.9)	36 (32.1)	76 (67.9)

Table 2.

Quantitative concentration analysis of imatinib for each dose

	100 mg dose study	400 mg dose study
HPLC	Nanospace SI-2, Shiseido, Japan	Nanospace SI-2, Shiseido, Japan
MS/MS	API 4000, AB SCIEX, USA	4000 QTRAP, AB SCIEX, USA
Linear calibration curve	3–1,500 ng/mL	5–5,000 ng/mL
LLOQ	3 ng/mL	5 ng/mL
Precision (CV%)	<15, <20 at LLOQ	<15, <20 at LLOQ
Accuracy (%)	85–115, 80–120 at LLOQ	85–115, 80–120 at LLOQ

HPLC, High-performance liquid chromatography; MS, mass spectrometry; LLOQ, lower limit of quantification.

Table 3.

Summary of basic model building steps

Model steps
NONMEM subroutines	OFV	Parameters estimated
first-order absorption, 1-compartment distribution
ADVAN2 TRANS2	15732.266	^θ_CL, θ_V, θ_ka ω_CL, ω_V, ω_ka
first-order absorption, 2-compartment distribution
ADVAN4 TRANS4	15279.718	^θ_CL, θ_V, θ_Vp, θ_Q, θ_ka ω_CL, ω_Vc, ω_Vp, ω_Q, ω_ka
zero-order absorption, 2-compartment distribution
ADVAN3 TRANS4	15851.349	^θ_CL, θ_Vc, θ_Vp, θ_Q, θ_D ω_CL, ω_Vc, ω_Vp, ω_Q, ω_D
Weibull absorption, 2-compartment distribution
ADVAN6	14234.527	^θ_CL, θ_Vc, θ_Vp, θ_Q, θ_KA1, θ_GA ^ω_CL, ω_Vc, ω_Vp, ω_Q, ω_KA1, ω_GA

OFV, objective function value; θ_CL, THETA for clearance; θ_V, THETA for volume of distribution; θ_Vc, THETA for central volume of distribution; θ_Vp, THETA for peripheral volume of distribution; θ_Q, THETA for inter-compartmental clearance; θ_D, THETA for absorption duration; θ_ka, THETA for absorption rate constant; θ_KA1, THETA for apparent absorption rate constant of Weibull function; θ_GA, THETA for shape factor of Weibull function; ω_CL, ETA for clearance; ω_V, ETA for volume of distribution; ω_Vc, ETA for central volume of distribution; ω_Vp, ETA for peripheral volume of distribution; ω_Q, ETA for inter-compartmental clearance; ω_D, ETA for absorption duration; ω_ka, ETA for absorption rate constant; ω_KA1, ETA for apparent absorption rate constant of Weibull function; ω_GA, ETA for shape factor of Weibull function.

Table 4.

Summary of covariate model building steps

Model step	OFV	∆OFV to base model	Variables screened by GAM	Significant
Base model
1	14234.527	NA
Covariate screening
2	14232.466	–2.061	Bwt on CL	Not significant
3	14226.851	–7.676	Age on Vc	Significant
5	14223.151	–11.376	Age, Bwt on Vc	Not significant
6	14228.543	–5.984	Bwt on Vp	Significant
7	14224.34	–10.187	Bwt, age on Vp	Not significant
8	14224.741	–9.786	age on Q	Significant
10	14230.548	–3.979	Bwt on GAMMA	Significant
11	14226.861	–7.666	Bwt, age on GAMMA	Not significant
Full model
12	14209.911	–24.616
Final model: Simultaneous inclusion of significant covariates
13	14219.532	–14.995	Age on Vc and Q

OFV, objective function value; GAM, generalized additive model; NA, not available; Bwt, body weight; CL, clearance; Vc, central volume of distribution; Vp, peripheral volume of distribution; Q, inter-compartmental clearance; GAMMA; shape factor of Weibull function.

Table 5.

Population pharmacokinetic parameters of imatinib

Parameter (unit)		Estimate	SE (% RSE)	Bootstrap median (95% CI)
Fixed effects
Apparent clearance model (CL/F)
CL = θ₁
θ₁	CL/F (L/h)	13.6	0.379 (2.79)	13.6 (13.572–13.611)
Apparent central volume model (Vc/F)
Vc = θ₂ × (Age/24)θ₉
^θ₂	Vc/F (L)	153	5.55 (3.63)	153 (152.750–153.366)
^θ₉	Age on Vc	0.312	0.147 (47.12)	0.309 (0.297–0.312)
Apparent peripheral volume model (Vp/F)
Vp = θ₃
θ₃	Vp (L)	64	3.58 (5.59)	63.5 (63.356–63.811)
Inter-compartmental clearance (Q/F)
Q = θ₄ × (Age/24)θ₁₀
^θ₄	Q (L/h)	8.64	0.898 (10.39)	8.455 (8.443–8.567)
^θ₁₀	Age on Q	0.531	0.342 (64.41)	0.539 (0.554–0.593)
Scale parameter
KA1 = θ₅
^θ₅	Scale parameter	0.998	0.0751 (7.53)	1.01 (1.007–1.014)
Shape parameter
GAMMA = θ₆
^θ₆	Shape parameter	2.24	0.212 (9.46)	2.26 (2.249–2.270)
Random effects
Interindividual variability (Exponential model)
ω² 11	IIV on CL	0.0548	0.0067 (12.3)	0.0538 (0.0536–0.0547)
ω² 22	IIV on Vc	0.0852	0.0141 (16.55)	0.0835 (0.0824–0.0841)
ω² 12	Cov (CL, Vc)	0.0519	0.0075 (14.45)	0.5837 (0.5631–0.5765)
ω² 33	IIV on Vp	0.129	0.0284 (22.02)	0.1253 (0.1237–0.1282)
ω² 44	IIV on Q	0.448	0.0884 (19.73)	0.4238 (0.4093–0.4292)
ω² 34	Cov (Vp, Q)	0.212	0.0485 (22.88)	0.8028 (0.7924–0.8045)
ω² 55	IIV on scale parameter	0.362	0.0576 (15.91)	0.3624 (0.3620–0.3706)
ω² 66	IIV on shape parameter	0.483	0.102 (21.12)	0.4624 (0.4573–0.4693)
Residual error (Combined model)
σ² 1	Additive part, fixed	0.0001	–	–
σ² 2	Proportional part	0.108	0.00175 (1.64)	0.108 (0.1074–0.1079)

SE, standard error; RSE, relative standard error; CI, confidence interval.

Table 6.

Summary of PPK studies reviewed

References	Absorption model	Distribution model	Subject number	Subjects characteristics	PK sampling	Dose (mg/m²)	Administration route	CL/F estimate (SE) (L/h)	V/F estimates (SE) (L)
[23]	Zero-order	One-	34	GIST	Pre-dose, 1–3 h, 6–9 h, 24 h (day 1), day 30, day 60	400–600	PO	7.97	168
[27]	Zero-order	One-	73	GIST	Pre-dose, 1–3 h, 6–9 h, 24 h (day 1), day 29	400–600	IM	8.18	168 + 58.5 (day 28)
[24] (Model1)	Zero-order	One-	43	GIST Soft tissue sarcoma	Pre-dose, 1, 2, 3, 4, 8, 12,14, 24 h (day 1)	300, 400, 500	–	9.33 (0.98)	184 (14)
[24] (Model2)	Zero-order	One-	42	GIST Soft tissue sarcoma	Pre-dose, 2, 8, 24h (day29) Pre-dose, 2, 4h (extension phase)	300, 400, 500	–	10.6 (1.16)	183 (16)
[25]	Zero-order	One-	31	CML Osteosarcoma Ewing sarcoma Desmoplastic small round cell tumor Synovial cell sarcoma GIST of young adult and children	Pre-dose, 1–3 h, 6–9 h, 12 h, 24 h over 24–48 h (day1, 8, 18)	260–570	PO	10.3	251
[13]	First-order	One-	67	GIST of adult and children	Adult: Pre-dose, 1–3 h, 6–9 h, 24 h (day 1), day 30, day 60 Children: Pre-dose, 1, 3, 5, 7, 13, 24 h (day 1) Pre-dose, 2–4 h (day 30, 60)	400, 600	PO	7.29	202
[15]	Zero-order	One-	553	CML	Pre-dose, 1–3 h, 6–9 h, 24 h (day 1, 29)	400	PO	13.8	252
[14]	First-order	One-	59	GIST CML ALL	Pre-dose, 2, 4, 6, 8 h	150–800	–	14.3	347
[26]	First-order	One-	34	CML	0–1 h, 0–8 h, 8–16 h, 16–30.5 h	100–600	–	8.7(5.3)	430 (9.9)
Our results	Weibull function	Two-	112	Healthy volunteers	Predose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 60 and 72 h (at 400 mg group only)	100, 400	PO	13.6 (0.379)	153 (5.55)^∗ 64 (3.58)^†

^∗Central compartment volume, ^†Peripheral compartment volume. One-, one-compartment; Two-, two-compartment; GIST, gastrointestinal stromal tumor; CML, chronic myeloid leukemia; AML; acute myeloid leukemia.

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