NDLI: Pharmacokinetic modeling of simvastatin, nelfinavir and their interaction in humans

Content Provider	IEEE Xplore Digital Library
Author	Methaneethorn, J. Kunyamee, P. Jindasri, W. Wattanasaovaluk, W. Kraiboot, A. Lohitnavy, M.
Copyright Year	2014
Description	Author affiliation: Pharmacokinetic Res. Unit, Naresuan Univ., Phitsanulok, Thailand (Methaneethorn, J.; Kunyamee, P.; Jindasri, W.; Wattanasaovaluk, W.; Kraiboot, A.; Lohitnavy, M.)
Abstract	Background: Simvastatin, a commonly used HMG-CoA reductase inhibitor, is extensively metabolized by CYP3A4. Therefore, co-administration of simvastatin and CYP3A4 inhibitor can affect simvastatin pharmacokinetics. Nelfinavir, a protease inhibitor, and its major metabolite (M8) are known to be potent CYP3A4 inhibitors. When simvastatin and nelfinavir are co-administered, simvastatin pharmacokinetics is significantly altered and may result in an increased risk of rhabdomyolysis. Objective: To develop a mathematical model describing a drug-drug interaction between simvastatin and nelfinavir in humans. Methods: Eligible pharmacokinetic studies were selected from Pubmed database and concentration time course data were digitally extracted and used for model development. Compartmental pharmacokinetic models for simvastatin and nelfinavir were developed separately. A drug-drug interaction model of simvastatin and nelfinavir was subsequently developed using the prior information. Finally, the final drug-drug interaction modeled was validated against observed simvastatin concentrations. Results: Three compartmental pharmacokinetic models were successfully developed. Simvastatin pharmacokinetics was best described by a one compartment model for simvastatin linked to its active form, simvastatin hydroxy acid. Nelfinavir pharmacokinetics could be adequately described by a one compartment parent-metabolite model. Our final drug-drug interaction model predicted an increase in simvastatin exposure which is in line with clinical observations linking the simvastatin-nelfinavir combination to an increased risk of rhabdomyolysis. Conclusion: Simvastatin-nelfinavir pharmacokinetic interaction can be explained by our final model. This model framework will be useful in further advanced developing other mechanism based drug-drug interaction model used to predict the risk of rhabdomyolysis occurrence in patients prescribed simvastatin and nelfinavir concurrently.
Sponsorship	IEEE Eng. Med. Biol. Soc.
Starting Page	5715
Ending Page	5718
File Size	803097
Page Count	4
File Format	PDF
ISBN	9781424479290
ISSN	1557170X
DOI	10.1109/EMBC.2014.6944925
Language	English
Publisher	Institute of Electrical and Electronics Engineers, Inc. (IEEE)
Publisher Date	2014-08-26
Publisher Place	USA
Access Restriction	Subscribed
Rights Holder	Institute of Electrical and Electronics Engineers, Inc. (IEEE)
Subject Keyword	Drugs Inhibitors Biochemistry Biological system modeling Human immunodeficiency virus Computational modeling Predictive models
Content Type	Text
Resource Type	Article
Subject	Signal Processing Biomedical Engineering Health Informatics Computer Vision and Pattern Recognition

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