title: Implication of the peak serum level of mizoribine for control of the serum anti-dsDNA antibody titer in patients with lupus nephritis.
abstract: OBJECTIVE
  Mizoribine (MZR) is a novel selective inhibitor of inosine monophosphatase dehydrogenase that was developed in Japan. We previously reported the efficacy and safety of oral MZR pulse therapy, which is associated with elevated peak serum MZR levels, in selected patients with lupus nephritis. However, only limited information is available as yet on the optimal peak serum level of MZR that would yield an enhanced clinical efficacy without serious toxicity in patients with lupus nephritis.
  
  
  METHODS
  A total of 11 patients with clinically stable lupus nephritis treated with oral MZR pulse therapy combined with low-dose prednisolone were enrolled in the cross-sectional study. The peak serum concentrations of MZR (as determined by HPLC) and the serum anti-dsDNA antibody titers (as determined by ELISA) were examined in the patients in order to evaluate the correlation between these two parameters. The correlation between the dose of MZR (mg/kg) administered orally as a single daily dose and the peak serum level of the drug was also examined. In two of the patients, serial measurements of the changes in the peak serum levels of MZR and anti-dsDNA titers could be conducted over 10 months.
  
  
  RESULTS
  A significant inverse correlation (r = -0.596, p = 0.0116) was observed between the peak serum levels of MZR and the serum anti-dsDNA antibody titers in the study participants, while the dose of prednisolone remained unchanged. The peak level of MZR in the serum was significantly correlated with the single dose of MZR (r = 0.509, p = 0.0371). In the two patients in whom serial measurements were conducted, the first patient who showed a peak serum MZR level of less than 2.5-3.0 microg/ml eventually developed an increase of the serum anti-dsDNA titer with hypocomplementemia and proteinuria. On the other hand, in the second patient who showed a peak serum MZR level in excess of 4.0 microg/ml, persistently low serum anti-dsDNA titers with normocomplementemia were observed.
  
  
  CONCLUSIONS
  Although this study is only a preliminary study conducted on a small sample, we speculate from the results that a peak serum level of MZR of at least more than 2.5-3.0 mirog/ml is necessary to achieve satisfactory clinical efficacy of the drug for the treatment of lupus nephritis. Further study is needed to confirm these preliminary findings.
authors.affiliation: Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan. hirotana@cc.hirosaki-u.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: K
authors.initials: K
authors.lastname: Tsugawa
authors.forename: T
authors.initials: T
authors.lastname: Nakahata
authors.forename: M
authors.initials: M
authors.lastname: Kudo
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: E
authors.initials: E
authors.lastname: Ito
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000974:Antibodies, Antinuclear / Q000097:blood*; D002648:Child; D002851:Chromatography, High Pressure Liquid; D003430:Cross-Sectional Studies; D004247:DNA / Q000276:immunology*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D005938:Glucocorticoids / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008181:Lupus Nephritis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D011239:Prednisolone / Q000627:therapeutic use; D012263:Ribonucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D000974:Antibodies, Antinuclear; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D004247:DNA; D011239:Prednisolone