Journal List > Transl Clin Pharmacol > v.24(2) > 1082649

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

Abstract

Imatinib (GleevecTM; 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.

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Figure 1.
Pharmacokinetic model for imatinib.
tcp-24-96f1.tif
Figure 2.
Scatterplots representing correlation between ETAs.
tcp-24-96f2.tif
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.
tcp-24-96f3.tif
Figure 4.
Visual predictive checks of the final PK model classified by dose of 100 mg and 400 mg.
tcp-24-96f4.tif
Table 1.
Study-subjects demographic characteristics
Study Subjects N (%) Samples N (%) Sampling points (h) Age (years) mean (range) Weight (kg) mean (range) Dose N (%)
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 θCL, θV, θka
ωCL, ωV, ωka
first-order absorption, 2-compartment distribution  
ADVAN4 TRANS4 15279.718 θCL, θV, θVp, θQ, θka
ωCL, ωVc, ωVp, ωQ, ωka
zero-order absorption, 2-compartment distribution  
ADVAN3 TRANS4 15851.349 θCL, θVc, θVp, θQ, θD
ωCL, ωVc, ωVp, ωQ, ωD
Weibull absorption, 2-compartment distribution  
ADVAN6 14234.527 θCL, θVc, θVp, θQ, θKA1, θGA
ωCL, ωVc, ωVp, ωQ, ωKA1, ωGA

OFV, objective function value; θCL, THETA for clearance; θV, THETA for volume of distribution; θVc, THETA for central volume of distribution; θVp, THETA for peripheral volume of distribution; θQ, THETA for inter-compartmental clearance; θD, THETA for absorption duration; θka, THETA for absorption rate constant; θKA1, THETA for apparent absorption rate constant of Weibull function; θGA, THETA for shape factor of Weibull function; ωCL, ETA for clearance; ωV, ETA for volume of distribution; ωVc, ETA for central volume of distribution; ωVp, ETA for peripheral volume of distribution; ωQ, ETA for inter-compartmental clearance; ωD, ETA for absorption duration; ωka, ETA for absorption rate constant; ωKA1, ETA for apparent absorption rate constant of Weibull function; ωGA, 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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