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Pharmacokinetics of the CYP 3A Substrate Simvastatin following Administration of Delayed Versus Immediate Release Oral Dosage Forms

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Abstract

Purpose

The study was designed to evaluate the effect of delayed release (DR) on absorption and bioavailability of intestinally metabolized drugs after oral dosing, using the HMG-CoA reductase inhibitor simvastatin, a CYP3A substrate, as a model drug.

Materials and Methods

To target drug release and to assess regional gastrointestinal absorption of the CYP 3A substrate simvastatin from the distal parts of the intestine, delayed release film coated tableted oral dosage forms were developed. Simvastatin delayed release tablet, simvastatin immediate release capsule and simvastatin immediate release tablet Zocor® were administered as single doses (20 mg) to fasting healthy volunteers in a crossover design.

Results

Simvastatin bioavailability was increased by a factor of three, as compared to the reference formulation Zocor®. The overall metabolite levels from the immediate release capsules tended to be higher throughout the period studied than the metabolite levels following administration of Zocor® and simvastatin delayed release dosage form.

Conclusions

The interplay between gastrointestinal physiology (lower CYP 3A expression in the distal ileum and the colon) and formulation design (zero-order controlled release after a predetermined lag-time) resulted in successful absorption and bioavailability improvement and represent a viable strategy to reduce the dose of CYP 3A drugs.

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Acknowledgements

The authors wish to thank Dr. Elke Lipka, TSRL Inc. for kindly revising the manuscript and Ute Hartung, Johannes Gutenberg-University Mainz, for helpful technical assistance.

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Authors and Affiliations

  1. Department of Pharmaceutical Technology and Biopharmaceutics, Johannes Gutenberg-University, Staudinger Weg 5, 55099, Mainz, Germany

    Marija Tubic-Grozdanis & Peter Langguth

  2. TSRL, Inc., 540 Avis Drive, Suite A, Ann Arbor, Michigan, 48108, USA

    John M. Hilfinger, Jae Seung Kim & Paul Kijek

  3. College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan, 48109-1065, USA

    Gordon L. Amidon

  4. Department of Dermatology University Hospital Mainz, Clinical Research Center, Langenbeckstr.1, 55101, Mainz, Germany

    Petra Staubach

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  1. Marija Tubic-Grozdanis
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Correspondence to Peter Langguth.

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Tubic-Grozdanis, M., Hilfinger, J.M., Amidon, G.L. et al. Pharmacokinetics of the CYP 3A Substrate Simvastatin following Administration of Delayed Versus Immediate Release Oral Dosage Forms. Pharm Res 25, 1591–1600 (2008). https://doi.org/10.1007/s11095-007-9519-6

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  • DOI: https://doi.org/10.1007/s11095-007-9519-6

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