title: Cyclosporin C(2) and C(0) concentration monitoring in stable, long-term heart transplant recipients receiving metabolic inhibitors.
abstract: BACKGROUND
  Cyclosporin (CsA) dose selection is complicated by significant pharmacokinetic variability between patients. Although therapeutic drug monitoring (TDM) has proven to be a useful tool for dose individualization, the search for an effective and practical measure of clinical effect has uncovered a number of options. Monitoring the CsA concentration in a blood sample taken 2 hours after the dose (C(2)) has been utilized but has not been rigorously evaluated in all clinical situations. The aim of this study was to evaluate C(2) and trough (C(0)) CsA concentrations as surrogate markers of area under the concentration-time curve (AUC) in stable, long-term heart transplant recipients receiving CsA alone or with diltiazem and/or ketoconazole.
  
  
  METHODS
  CsA blood concentration-time data were collected at steady state for 47 stable heart transplant recipients after the morning dose of Neoral. CsA concentration in whole blood was quantitated using the EMIT immunoassay. Patients were stratified into 4 groups, depending on the long-term concomitant administration of drugs known to inhibit CsA metabolism, as part of their routine therapy: Group A (n = 11), CsA alone; Group B (n = 10), CsA with slow-release diltiazem; Group C (n = 13), CsA with ketoconazole; and Group D (n = 12), CsA with a combination of diltiazem and ketoconazole.
  
  
  RESULTS
  In Group A, C(2) correlated poorly with AUC(0-5) (r(2) = 0.197; p = 0.17), whereas C(0) (trough blood sample) showed a stronger correlation (r(2) = 0.710; p = 0.001). Correlations of C(0) and C(2) with AUC(0-5) were the same, but weaker in patients receiving CsA and diltiazem (r(2) = 0.650; p = 0.005); however, C(2) correlated strongly with AUC(0-5) in patients receiving ketoconazole (r(2) = 0.870; p < 0.0001) or ketoconazole with diltiazem (r(2) = 0.898; p < 0.0001). C(0) was a poor predictor of AUC(0-5) in the latter 2 groups.
  
  
  CONCLUSIONS
  C(2) showed a strong correlation with AUC(0-5) in cardiothoracic transplant recipients receiving CsA with ketoconazole, but not with CsA alone or diltiazem. TDM using C(2) as an estimate of AUC requires further evaluation before being applied in long-term, stable cardiac transplant patients, as it may lead to inappropriate dose adjustment of CsA in patients receiving concomitant metabolic inhibitors.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, Institute of Laboratory Medicine, Sydney, Australia. jray@stvincents.com.au
authors.forename: John E
authors.initials: JE
authors.lastname: Ray
authors.forename: Anne M
authors.initials: AM
authors.lastname: Keogh
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
authors.forename: Fatemah
authors.initials: F
authors.lastname: Akhlaghi
mesh_terms: D000935:Antifungal Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D003524:Cyclosporins / Q000378:metabolism*; D004110:Diltiazem / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000378:metabolism* / Q000493:pharmacokinetics; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D013223:Statistics as Topic; D013995:Time; D013997:Time Factors
chemical_list: D000935:Antifungal Agents; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D004791:Enzyme Inhibitors; C100000:cyclosporin C; D016572:Cyclosporine; D004110:Diltiazem; D007654:Ketoconazole