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Genetic algorithm guided population pharmacokinetic model development for simvastatin, concurrently or non-concurrently co-administered with amlodipine

Authors

  • Ayyappa Chaturvedula PhD,

    1. Department of Bioengineering, Therapeutic Sciences, Center for Drug Development Science, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA
    Current affiliation:
    1. Departments of Pharmacy Practice & Pharmaceutical Sciences, Mercer University College of Pharmacy, Health Sciences, Atlanta, GA, USA
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  • Mark E. Sale MD,

    1. Next Level Solutions Inc., Raleigh, NC, USA
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  • Howard Lee MD, PhD

    Corresponding author
    1. Department of Bioengineering and Therapeutic Sciences, Center for Drug Development Science, School of Pharmacy, University of California San Francisco, San Francisco, CA, USA
    Current affiliation:
    1. Clinical Trials Center, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, Seoul, Korea
    • Corresponding Author:

      Professor Howard Lee, MD, PhD, Clinical Trials Center, Department of Clinical Pharmacology and Therapeutics, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea

      Email: howardlee@snu.ac.kr

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  • Prior presentations: The abstract entitled, “Development of population pharmacokinetic model for simvastatin and amlodipine interaction guided by single objective hybrid genetic algorithm” was presented at the 2012 annual meeting of American College of Clinical Pharmacology.

Abstract

An automated model development was performed for simvastatin, co-administered with amlodipine concurrently or non-concurrently (i.e., 4 hours later) in 17 patients with coexisting hyperlipidemia and hypertension. The single objective hybrid genetic algorithm (SOHGA) was implemented in the NONMEM software by defining the search space for structural, statistical and covariate models. Candidate models obtained from the SOHGA runs were further assessed for biological plausibility and the precision of parameter estimates, followed by traditional backward elimination process for model refinement. The final population pharmacokinetic model shows that the elimination rate constant for simvastatin acid, the active form by hydrolysis of its lactone prodrug (i.e., simvastatin), is only 44% in the concurrent amlodipine administration group compared with the non-concurrent group. The application of SOHGA for automated model selection, combined with traditional model selection strategies, appears to save time for model development, which also can generate new hypotheses that are biologically more plausible.

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