title: Correlation Between C2 and AUC(0-4) in Renal Transplant Patients Treated With Diltiazem.
abstract: BACKGROUND
  The area-under-the-curve (AUC) of cyclosporine (CsA) reflects exposure to the drug, but this monitoring strategy is time-consuming and not cost-effective. Recently, it has been suggested that the concentration at 2 hours after dosing (C2) shows the best correlation with AUC. The C2 has been replacing the trough measurement (C0) to monitor CsA therapy, but in patients receiving diltiazem there is not much information about this issue. We investigated the correlations between C2 and C0 with absorption AUC over the first 4 hours (AUC(0-4)) in renal stable transplant patients receiving CsA therapy with or without diltiazem.
  
  
  METHODS
  Ten patients (five men) of ages 23 to 68 years and 6 to 84 months after transplantation, were randomly assigned to an 8-week initial period of either diltiazem washout or controlled treatment with diltiazem. Time-concentration curves of cyclosporine were performed at the end of this period using a specific RIA measurement of blood samples. Thereafter, a crossover of the groups was performed and after another 8 weeks, a second curve was obtained. Drugs that change the pharmacokinetics of cyclosporine or diltiazem were not allowed.
  
  
  RESULTS
  The cyclosporine daily dose was lower with diltiazem (173 +/- 4 mg vs 213 +/- 4 mg, P = .002), but despite a dose reduction of only 19% +/- 1.5%, there was a trend to a larger AUC/dose (28 +/- 5 ng x h/mL x mg vs 17 +/- 2 ng x h/mL x mg, P = .1) and a trend to an increased C2 when treatment included diltiazem (1035 +/- 156 ng/mL vs 652 +/- 126 ng/mL, P = NS). Moreover, we confirmed that C2 showed the best correlation with AUC(0-4), (r = 0.7, P = .04), a correlation that improved with diltiazem (r = 0.9, P < .002).
  
  
  CONCLUSIONS
  C2 is the point that correlates best with AUC(0-4) with or without diltiazem. C2 in the presence of diltiazem was associated with a stronger, more significant correlation with AUC(0-4).
authors.affiliation: Nephrology Department, University Austral Medical School, Valdivia, Chile. claudioaros@uach.cl
authors.forename: C A
authors.initials: CA
authors.lastname: Aros
authors.forename: H O
authors.initials: HO
authors.lastname: Schneider
authors.forename: C A
authors.initials: CA
authors.lastname: Flores
authors.forename: L G
authors.initials: LG
authors.lastname: Ardiles
authors.forename: P A
authors.initials: PA
authors.lastname: Alruiz
authors.forename: V
authors.initials: V
authors.lastname: Jerez
authors.forename: S A
authors.initials: SA
authors.lastname: Mezzano
mesh_terms: D000328:Adult; D000368:Aged; D019540:Area Under Curve; D016572:Cyclosporine / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004110:Diltiazem / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008875:Middle Aged; D014665:Vasodilator Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D016572:Cyclosporine; D004110:Diltiazem