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Population Pharmacokinetic Analysis of Simvastatin and its Active Metabolite with the Characterization of Atypical Complex Absorption Kinetics

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Abstract

Purpose

The pharmacokinetics of simvastatin is complex with multiple peaks in the absorption phase, which cannot be adequately described by a conventional first order absorption model. The biotransformation of simvastatin into simvastatin acid, an active metabolite, is reversible. This study evaluated the pharmacokinetics of simvastatin and simvastatin acid, focusing on the absorption kinetics.

Methods

Data were collected from three bioequivalence studies, in which subjects were administered 60 mg simvastatin, and from one crossover study, in which subjects were administered two doses randomly selected from 10, 20, 30, 40 to 80 mg simvastatin with washout period. The pharmacokinetics of simvastatin was assessed in 133 healthy males. Plasma concentrations of simvastatin and simvastatin acid were measured in 2,182 and 2,130 samples, respectively, and the pharmacokinetic data were analyzed using NONMEM.

Results

The time course of changes in the plasma simvastatin concentration was best described by a two-compartment linear model with three parallel absorption processes, each of which consisted of mixed zero-and first order absorption. Additions of inter-occasional variability to the absorption parameters significantly improved the model’s fit. The disposition parameter estimates were significantly different when different absorption models were applied, indicating the importance of the appropriate absorption modeling. Pharmacokinetic modeling preferred the inter-conversion between simvastatin and simvastatin acid.

Conclusion

A pharmacokinetic model describing the complex, multiple peak, absorption kinetics of simvastatin was formulated using three parallel, mixed zero and first-order absorptions. This type of absorption model may be applicable to other drugs that show irregular, multiple-peak concentrations during their absorption phase.

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Abbreviations

A(n):

Amount of drug in nth compartment

ALAGn:

Absorption lag from nth compartment

CL:

Clearance

CV:

Coefficient of variation

Dn:

Duration of zero order administration to nth Depot compartment

FM:

Fraction that is metabolized to simvastatin acid of total clearance of simvastatin

Fn:

Bioavailability to nth depot compartment

FOCE:

First-order conditional estimation

GOF:

Goodness-of-fit

HMG-CoA:

3-hydroxy-3-methylglutaryl coenzyme A

IIV:

Inter-individual variability

IOV:

Inter-occasional variability

K:

Transfer rate constant between pharmacokinetic compartment

Ka:

Absorption rate constant

LLOQ:

Lower limit of quantification

LOWESS:

Locally weighted scatterplot smoothing

MAP:

Maximum a posteriori probability

OFV:

Objective function value

Q:

Inter-compartmental clearance between central and peripheral compartment

Vd:

Volume of distribution

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Acknowledgments and Disclosures

This study was supported by Daewoong Corporation, South Korea, and a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI07C0001). The authors declare they have no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Pungnap-2-dong, 88 Olympic-ro 43-gil, Sonpa-gu, Seoul, 138-736, Korea

    Kyun-Seop Bae, Unjib Kim & Hyeong-Seok Lim

  2. Department of Anesthesiology, Ulsan University College of Medicine Asan Medical Center, Pungnap-2-dong, 88 Olympic-ro 43-gil, Sonpa-gu, Seoul, 138-736, Korea

    Seok-Joon Jin

  3. Department of Clinical Pharmacology, Inha University Hospital Inha University School of Medicine, Incheon, Republic of Korea

    Sang-Heon Cho

  4. Department of Clinical Pharmacology and Therapeutics, Samsung Medical Center, Seoul, Republic of Korea

    Jin-Ah Jung

  5. Division of Clinical Pharmacology, Clinical Trials Center, Pusan National University Hospital, Busan, Republic of Korea

    Sangmin Choe

  6. Department of Pharmacology, Inje University College of Medicine, Busan, Republic of Korea

    Jong-Lyul Ghim & Yook-Hwan Noh

  7. Pharmacokinetic & Pharmacogenetic Laboratory Clinical Research Center, Asan Medical Center, Pungnap-2-dong, Seoul, Republic of Korea

    Hyun-Jung Park

  8. Daewoong Pharmaceutical Company, Seoul, Republic of Korea

    Hee-sun Kim

Authors
  1. Seok-Joon Jin
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  2. Kyun-Seop Bae
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  3. Sang-Heon Cho
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  4. Jin-Ah Jung
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  7. Jong-Lyul Ghim
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  9. Hyun-Jung Park
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  10. Hee-sun Kim
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  11. Hyeong-Seok Lim
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Corresponding author

Correspondence to Hyeong-Seok Lim.

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Jin, SJ., Bae, KS., Cho, SH. et al. Population Pharmacokinetic Analysis of Simvastatin and its Active Metabolite with the Characterization of Atypical Complex Absorption Kinetics. Pharm Res 31, 1801–1812 (2014). https://doi.org/10.1007/s11095-013-1284-0

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  • DOI: https://doi.org/10.1007/s11095-013-1284-0

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