A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis
A lack of published pharmacokinetic data on statins in sepsis has prompted concerns about their safety and toxicity. This study determined single dose pharmacokinetics of Atorvastatin administered orally to acutely ill patients.
Design, setting and participants
A prospective open label study conducted in a tertiary referral centre on 5 healthy volunteers, 5 acutely ill patients admitted to the medical ward and a heterogeneous cohort of 25 critically ill patients admitted to an intensive care unit.
All participants received a single oral dose of 20 mg of atorvastatin.
Measurement and results
Plasma pharmacokinetics of atorvastatin as measured by maximal plasma concentration (Cmax) and area under the curve (AUC) 0–24 h. Critically ill patients with sepsis had a significantly higher Cmax and AUC as compared to healthy volunteers [110.5(86.5) vs. 5.9(2.50) ng/ml, p < 0.01 and 1,051(810) vs. 67(48) ng h/ml (p < 0.0001)], respectively. Atorvastatin concentrations in the plasma of critically ill patients with sepsis remained supratherapeutic for up to 20 h after a single dose. The AUC was significantly higher for those patients on concomitant CYP 450 inhibitor therapy as compared to those patients not on inhibitors (1,518 ± 793 vs. 584 ± 540 ng h/ml, p = 0.0260).
Very high plasma concentrations were achieved in intensive care patients with sepsis. This can only be partly explained by altered metabolism of atorvastatin. Further investigations are essential to better describe the pharmacokinetics of statins in various groups of critically ill patients. Caution should be exercised prior to adopting high dose regimens in patients with severe sepsis.
KeywordsStatin Pharmacokinetics Sepsis Critical illness
This work was supported by a grant from the Princess Alexandra Hospital Research Foundation and Australian National Health and Medical Research Council. Professor Roberts has received a research grant from Pfizer through the University of Queensland for unrelated transdermal research. All other authors have no financial or personal relationships that could inappropriately influence this work. Pfizer has provided no support for this study. All authors have seen and approved the final manuscript version. P. K. was involved in study design, patient enrolment, data analysis and manuscript preparation. N. F. was involved in patient enrolment and sample collection. B. V. was involved in study design, data analysis and manuscript preparation. M. R. was involved in study design, assay quality assurance, data analysis and manuscript preparation. T. R. was involved in assay development and sample analysis. M. J. was involved in the statistical analysis of results.
- 1.Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 366:1267–1278PubMedCrossRefGoogle Scholar
- 6.The STATInS trial: Statins in Sepsis Study 2007 ACTRN 12607000028404. http://www.anzctr.org.au/trial_view.aspx?ID=81692
- 7.The CAS trial: Continued use of Atorvastatin in sepsis 2006 ACTRN12605000756628. http://www.anzctr.org.au/trial_view.aspx?ID=886
- 11.Australian Institute of health and welfare (2006) Top 10 drugs Australian Prescriber 29; 1: 5Google Scholar
- 12.Macin SM, Perna ER, Farias EF, Franciosi V, Cialzeta JR, Brizuela M, Medina F, Tajer C, Doval H, Badaracco R (2005) Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study. Am Heart J 149:451–457PubMedCrossRefGoogle Scholar
- 14.Jemal M, Ouyang Z, Chen BC, Teitz D (1999) Quantitation of the acid and lactone forms of atorvastatin and its biotransformation products in human serum by high-performance liquid chromatography with electrospray tandem mass spectrometry. Rapid Commun Mass Spectrom 13:1003–1015PubMedCrossRefGoogle Scholar