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Clinical Pharmacokinetics

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01-10-2010 | Original Research Article

Development of a Population Pharmacokinetic Model for Atorvastatin Acid and Its Lactone Metabolite

Authors: Rajesh Narwal, Dr Fatemeh Akhlaghi, Anders Åsberg, Monica Hermann, Sara E. Rosenbaum

Published in: Clinical Pharmacokinetics | Issue 10/2010

Abstract

Background and Objectives

Atorvastatin lactone, a metabolite of the HMG-CoA reductase inhibitor (statin) atorvastatin acid, is believed to be myotoxic. Our objectives were to develop a population pharmacokinetic model for atorvastatin acid and its lactone metabolite and to identify patient characteristics that are predictive of variability in the pharmacokinetic parameters of the parent drug and its lactone metabolite.

Subjects and Methods

Twenty-six subjects, 13 of whom had experienced atorvastatin-induced myopathy, received atorvastatin 10mg once daily for 7 days. Plasma samples taken on day 7 at 0 hours (predose) and 0.5, 1, 1.5, 2, 3, 5, 7, 9, 12, 22 and 24 hours post-dose were analysed for both atorvastatin acid and atorvastatin lactone, using a validated liquid chromatography assay with tandem mass spectrometry, and the data were modelled using nonlinear mixed-effects modelling software (NONMEM®). The influence of the patients’ demographic characteristics, biochemical indices and pharmacogenomics was evaluated. Final model validation was carried out using a visual predictive check.

Results

The pharmacokinetics of atorvastatin acid and atorvastatin lactone were best described by two- and one-compartment models, respectively. The main pharmacokinetic parameters of atorvastatin acid (mean [relative standard error RSE]) for a subject with mean covariate values were the first-order absorption rate constant (3.5 h⁻¹ fixed); oral clearance (504 L/h [29%]); apparent volume of the central compartment (3250 L [16.5%]); and apparent volume of the peripheral compartment (2170 L [9.3%]). The main pharmacokinetic parameters of atorvastatin lactone (mean [RSE]) were the apparent clearance to atorvastatin acid (24 L/h [154%]); apparent total body clearance (116L/h [9.5%]); and apparent volume of distribution (137L [33.7%]). The value of aspartate transaminase was identified as a significant covariate for the apparent volume of the central compartment for atorvastatin acid and for the apparent total body clearance of atorvastatin lactone, signifying the importance of liver function in atorvastatin pharmacokinetics. The visual predictive plots demonstrated that the model adequately described the pharmacokinetics of both species.

Conclusion

A population pharmacokinetics model was developed and validated to describe atorvastatin acid and its lactone metabolite concentration-time data. This model may be useful for atorvastatin dose individualization or analysis of sparse data.

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Title: Development of a Population Pharmacokinetic Model for Atorvastatin Acid and Its Lactone Metabolite
Authors: Rajesh Narwal
Dr Fatemeh Akhlaghi
Anders Åsberg
Monica Hermann
Sara E. Rosenbaum
Publication date: 01-10-2010
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 10/2010
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.2165/11535980-000000000-00000

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Development of a Population Pharmacokinetic Model for Atorvastatin Acid and Its Lactone Metabolite

Abstract

Background and Objectives

Subjects and Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and Objectives

Subjects and Methods

Results

Conclusion

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