title: Cyclosporine A area-under-time-concentration-curve in rheumatologic patients after the first dose. Which of the sparse sampling strategies will predict the best?
abstract: OBJECTIVE
  The aim of the present study was to validate the limited sampling strategies (LSS:s) for prediction of AUC of cyclosporine A (CsA) after the first dose in rheumatologic patients.
  
  
  METHODS
  22 patients suffering from rheumathoid arthritis, systemic lupus erythematodus, ankylosing spondylitis dermato(poly)myositis or seronegative spondylarthritis were treated with Neoral® (female/male: 11/3, mean ± SD: age 49 ± 14 y, body weight 75 ± 12 kg, height 166 ± 7 cm, dose 71 ± 25 mg, dose per kg 1.0 ± 0.3 mg/kg), or Consupren® (7/1, 78 ± 36, 175 ± 8, 82 ± 22, 1.1 ± 0.3). Two patients whose C12h were missing were excluded from the AUC0-12 calculation. Whole blood levels of CsA were analyzed with HPLC. Blood samples were collected at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours after taking the first dose. Altogether 115 LSS:s obtained from the literature were validated. A linear trapezoidal rule was used as a reference method. Mean percentage prediction error (%PE) < ± 15% and maximal one value of absolute %PE > 30% were considered to be acceptable. The root mean squared error (RMSE) was evaluated for equations that passed the criteria.
  
  
  RESULTS
  The best performance with all values of the absolute %PE < 30% was found in three LSS:s for AUC0-12 and two for AUC0-8: AUC0-12 = 123.792 + 1.165 × C1h + 3.021 × C3h + 7.33 × C8h; 97.6 + 1.27 × C1h + 3.14 × C3h + 4.06 × C6h; or 124.3 + 1.34 × C1h - 0.16 × C2h + 3.27 × C3h + 3.96 × C6h; AUC0-8 = -19.8 + 1.99 × C2h + 2.38 × C4h + 3.15 × C6h or -22.4 + 2.51 × C2h + 5.49 × C6h. Validation criteria were further fulfilled in AUC0-12 = 24 + 3.66 × C0h + 2.11 × C1.5h + 4.54 × C4h or 0.2 + 2 × C2h + 10.2 × C6h; AUC0-8 = 55.37 + 2.89 × C0h + 1.08 × C1 + 0.9 × C2h + 2.23 × C3h; and AUC0-4 = -41 + 1.17 × C1h + 1.85 × C2h. Only one equation proposed for AUC0-6 did not pass the validation criteria.
  
  
  CONCLUSIONS
  Equations validated for prediction of AUC0-12, AUC0-8 and AUC0-4 might be used for LSS:s of CsA independently of the length of treatment, indication, dosage or galenic formulation.
authors.affiliation: Department of Clinical Pharmacology, Ostrava University Hospital and Medical Faculty, University of Ostrava, Ostrava, Czech Republic. blanka.koristkova@seznam.cz
authors.forename: B
authors.initials: B
authors.lastname: Koristkova
authors.forename: M
authors.initials: M
authors.lastname: Grundmann
authors.forename: D
authors.initials: D
authors.lastname: Suchy
authors.forename: I
authors.initials: I
authors.lastname: Perinova
authors.forename: H
authors.initials: H
authors.lastname: Brozmanova
authors.forename: O
authors.initials: O
authors.lastname: Mayer
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012216:Rheumatic Diseases / Q000378:metabolism*
chemical_list: D018501:Antirheumatic Agents; D016572:Cyclosporine