Reversible elevations of serum creatinine levels but no effect on glomerular filtration during treatment with the direct thrombin inhibitor AZD0837

Eur J Clin Pharmacol. 2010 Sep;66(9):903-10. doi: 10.1007/s00228-010-0849-7. Epub 2010 Jun 10.


Purpose: Reversible mean increases in serum creatinine (approx. 10%) have been observed during clinical investigations of the oral direct thrombin inhibitor AZD0837. The aim of this study was to evaluate whether the increase in s-creatinine is due to a decrease in renal glomerular filtration rate (GFR) or an inhibition of the tubular secretion of creatinine.

Methods: Thirty healthy subjects aged 60-71 years were enrolled in an open-label, randomised, placebo-controlled, two-way crossover study (D1250C00033) in which they received AZD0837 450 mg extended-release formulation once daily for 8 days. Cimetidine was co-administered on Days 6-8 during both treatment periods. Blood and urine samples were collected for assessment of s-creatinine, s-cystatin C, endogenous creatinine clearance (CrCl) and urinary markers of renal damage. GFR was measured by the plasma clearance of iohexol.

Results: A 6% increase in mean s-creatinine, but no increase in s-cystatin C, was observed during treatment with AZD0837. Co-administration of cimetidine resulted in a 21% increase in s-creatinine. A significant decrease in CrCl was found during AZD0837 treatment compared with placebo [-5.73 ml/min; 95% confidence interval (CI) -11.3 to -0.12]. No significant difference in GFR (-1.6 ml/min/1.73 m(2); 90% CI -3.7 to 0.5) was seen during treatment with AZD0837 versus placebo. No changes in renal damage markers were found during the treatment periods.

Conclusions: An increase in s-creatinine and a decrease in CrCl, but no decrease in GFR, were found during treatment with AZD0837. These findings suggest that inhibition of the renal tubular secretion of creatinine is the likely cause of the observed increase in s-creatinine.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amidines / pharmacokinetics
  • Amidines / pharmacology*
  • Anti-Ulcer Agents / pharmacology
  • Area Under Curve
  • Azetidines / pharmacokinetics
  • Azetidines / pharmacology*
  • Biomarkers / blood
  • Cimetidine / pharmacology
  • Creatinine / blood*
  • Cross-Over Studies
  • Female
  • Fibrinolytic Agents / pharmacokinetics
  • Fibrinolytic Agents / pharmacology*
  • Glomerular Filtration Rate / drug effects*
  • Humans
  • Kidney Function Tests
  • Kidney Tubules / drug effects*
  • Kidney Tubules / metabolism
  • Male
  • Middle Aged
  • Stroke / etiology
  • Stroke / prevention & control
  • Thrombin / antagonists & inhibitors*


  • AZD 0837
  • Amidines
  • Anti-Ulcer Agents
  • Azetidines
  • Biomarkers
  • Fibrinolytic Agents
  • Cimetidine
  • Creatinine
  • Thrombin