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Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers

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Abstract

Background and Objective

Imatinib mesylate is presently the first-line treatment for chronic myeloid leukemia (CML). The aim of this study was to investigate the absorption and distribution kinetics of imatinib in healthy Iranian volunteers using nonlinear mixed effects modeling (NLMEM) to assess the overall, intra- and inter-subject variabilities in pharmacokinetic parameters after oral administration.

Methods

This analysis was based on data from 24 healthy subjects who participated in a bioequivalence study after administering a single dose of 200 mg of each formulation. Imatinib concentrations were quantified using a validated liquid chromatography method. To simultaneously describe the imatinib pharmacokinetic profiles obtained with both formulations, a population pharmacokinetic model was applied to data using SAEM algorithm implemented in MONOLIX, whilst simulations were used by numerical solving of ordinary differential equations to calculate secondary parameters in individuals for bioequivalence studies.

Results

According to goodness-of-fit criteria, a two-compartment open model with sequential zero- then first-order absorption and first-order elimination was used as the structural pharmacokinetic model. Inter-individual variability (IIV) was considered for all parameters. Typical population estimates (% IIV) were fraction of the drug absorbed with a zero-order kinetic (Fr) of 0.153 (47.9 %) in period (Tk0) of 0.714 h (47.4 %), first-order absorption rate constant (k a) of 0.94 h−1(31.2 %), oral clearance of 19 L/h (27.9 %), central volume of distribution (V c/F) of 139 L (21.5 %), apparent peripheral volume of distribution (V p/F) of 130 L (29.7 %) and the apparent inter-compartment clearance (Q/F) of 29.6 L/h (41.8 %). Body mass index (BMI) was the only covariate found to significantly affect V p /F. The coefficient of variation for intra-individual plasma exposure (AUC0–∞) was 27.8 %.

Conclusions

Analyses using NLMEM for imatinib exhibited absorption complexities such as two input rates and medium to high intra-individual variability in drug exposure.

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Acknowledgments

This study was part of a PhD thesis supported by Tehran University of Medical Sciences (TUMS).

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Authors and Affiliations

  1. Biopharmaceutics and Pharmacokinetic Division, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, 14155-651, Iran

    Ali-Akbar Golabchifar, Nahid Mobarghei Dinan & Mohammad-Reza Rouini

  2. Department of Pharmaceutics, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran

    Saeed Rezaee

  3. Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Abbas Kebriaeezadeh

Authors
  1. Ali-Akbar Golabchifar
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  2. Saeed Rezaee
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  3. Nahid Mobarghei Dinan
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  5. Mohammad-Reza Rouini
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Corresponding author

Correspondence to Mohammad-Reza Rouini.

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Funding

This study was financially supported by Osvah Pharmaceutical Co., Iran.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures in this study were in accordance with the 1964 Helsinki declaration. The study was approved by ethics committee of Tehran University of Medical Sciences.

Informed consent

All subjects gave written informed consent and details of study were explained to all volunteers.

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Golabchifar, AA., Rezaee, S., Dinan, N.M. et al. Population Pharmacokinetic Analysis of the Oral Absorption Process and Explaining Intra-Subject Variability in Plasma Exposures of Imatinib in Healthy Volunteers. Eur J Drug Metab Pharmacokinet 41, 527–539 (2016). https://doi.org/10.1007/s13318-015-0292-3

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