title: Development of a population pharmacokinetic model for atorvastatin acid and its lactone metabolite.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  Twenty-six subjects, 13 of whom had experienced atorvastatin-induced myopathy, received atorvastatin 10 mg 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 (116 L/h [9.5%]); and apparent volume of distribution (137 L [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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Narwal
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Akhlaghi
authors.forename: Anders
authors.initials: A
authors.lastname: Asberg
authors.forename: Monica
authors.initials: M
authors.lastname: Hermann
authors.forename: Sara E
authors.initials: SE
authors.lastname: Rosenbaum
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D050197:Atherosclerosis / Q000188:drug therapy*; D000069059:Atorvastatin; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D007783:Lactones / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011758:Pyrroles / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007783:Lactones; D011758:Pyrroles; D000069059:Atorvastatin
references.citation: Stroke. 2008 Dec;39(12):3297-302
references.pmid: 18845807
references.citation: Clin Pharmacol Ther. 2007 Feb;81(2):194-204
references.pmid: 17192770
references.citation: Clin Pharmacol Ther. 2009 Nov;86(5):497-502
references.pmid: 19571802
references.citation: Drug Metab Dispos. 2000 Nov;28(11):1369-78
references.pmid: 11038166
references.citation: Clin Pharmacokinet. 1996 May;30(5):329-32
references.pmid: 8743333
references.citation: Ann Pharmacother. 2001 Sep;35(9):1096-107
references.pmid: 11573861
references.citation: JAMA. 2004 Dec 1;292(21):2585-90
references.pmid: 15572716
references.citation: Ann Pharmacother. 2002 Feb;36(2):288-95
references.pmid: 11847951
references.citation: J Clin Invest. 1973 Jul;52(7):1533-43
references.pmid: 4718952
references.citation: Drug Metab Dispos. 2005 Apr;33(4):537-46
references.pmid: 15616150
references.citation: Arterioscler Thromb Vasc Biol. 1995 May;15(5):678-82
references.pmid: 7749881
references.citation: JAMA. 2003 Apr 2;289(13):1681-90
references.pmid: 12672737
references.citation: Eur J Cardiovasc Prev Rehabil. 2009 Apr;16(2):222-8
references.pmid: 19242355
references.citation: Pharm Res. 1993 Oct;10(10):1461-5
references.pmid: 8272408
references.citation: Clin Pharmacol Ther. 2004 Oct;76(4):388-91
references.pmid: 15470339
references.citation: Drug Metab Dispos. 2001 Oct;29(10):1251-5
references.pmid: 11560866
references.citation: J Pharmacol Exp Ther. 2006 Feb;316(2):762-71
references.pmid: 16258024
references.citation: JAMA. 1996 Jan 10;275(2):128-33
references.pmid: 8531308
references.citation: Clin Pharmacol Ther. 2010 Jan;87(1):65-73
references.pmid: 19794410
references.citation: Pharm Res. 2000 Feb;17(2):209-15
references.pmid: 10751037
references.citation: Drugs. 1997 May;53(5):828-47
references.pmid: 9129869
references.citation: N Engl J Med. 2008 Aug 21;359(8):789-99
references.pmid: 18650507
references.citation: Drug Metab Dispos. 2002 May;30(5):505-12
references.pmid: 11950779
references.citation: Clin Pharmacokinet. 2003;42(13):1141-60
references.pmid: 14531725
references.citation: Drug Metab Dispos. 2000 Nov;28(11):1335-42
references.pmid: 11038162
references.citation: Clin Pharmacol Ther. 2005 Aug;78(2):154-67
references.pmid: 16084850
references.citation: Anal Bioanal Chem. 2005 Jul;382(5):1242-9
references.pmid: 15933849
references.citation: Eur J Pharm Sci. 2008 Apr 23;33(4-5):317-25
references.pmid: 18294823
references.citation: J Clin Pharmacol. 1997 Sep;37(9):816-9
references.pmid: 9549635
references.citation: J Clin Pharmacol. 1996 Mar;36(3):242-6
references.pmid: 8690818
references.citation: Atherosclerosis. 1997 May;131(1):17-23
references.pmid: 9180240
references.citation: J Cell Mol Med. 2001 Oct-Dec;5(4):378-87
references.pmid: 12067471
references.citation: Clin Pharmacokinet. 1997 Nov;33(5):313-27
references.pmid: 9391745
references.citation: Clin Pharmacol Ther. 2009 Aug;86(2):197-203
references.pmid: 19474787
references.citation: Clin Pharmacol Ther. 2006 Jun;79(6):532-9
references.pmid: 16765141