Transl Clin Pharmacol.  2016 Jun;24(2):96-104. 10.12793/tcp.2016.24.2.96.

Population pharmacokinetics of imatinib mesylate in healthy Korean subjects

Affiliations
  • 1Department of Clinical Pharmacology and Therapeutics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea. yimds@catholic.ac.kr
  • 2PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, The Catholic University of Korea, Seoul 06591, Korea.

Abstract

Imatinib (Gleevecâ„¢; 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 firstorder 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), intercompartmental 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.

Keyword

Imatinib; population pharmacokinetics; NONMEM; Weibull

MeSH Terms

Absorption
Humans
Imatinib Mesylate*
Male
Methods
Pharmacokinetics*
Plasma
Protein-Tyrosine Kinases
Volunteers
Imatinib Mesylate
Protein-Tyrosine Kinases

Figure

  • 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.


Reference

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