title: Population Pharmacokinetics of Hydroxychloroquine in Japanese Patients With Cutaneous or Systemic Lupus Erythematosus.
abstract: BACKGROUND
  Hydroxychloroquine (HCQ) is an effective treatment for patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) and has been used for these patients in more than 70 nations. However, in Japan, HCQ has not been approved for CLE or SLE. To establish an appropriate therapeutic regimen and to clarify the pharmacokinetics (PK) of HCQ in Japanese patients with CLE with or without SLE (CLE/SLE), a population pharmacokinetic (PopPK) analysis was performed.
  
  
  METHODS
  In a clinical study of Japanese patients with a diagnosis of CLE irrespective of the presence of SLE, blood and plasma drug concentration-time data receiving multiple oral doses of HCQ sulfate (200-400 mg daily) were analyzed using nonlinear mixed-effects model software. The blood and plasma concentrations of HCQ were analyzed using a high-performance liquid chromatography tandem mass spectrometry method. Model evaluation and validation were performed using goodness-of-fit (GOF) plots, visual predictive check, and a bootstrap.
  
  
  RESULTS
  The PopPKs of HCQ in the blood and plasma of 90 Japanese patients with CLE/SLE were well described by a 1-compartment model with first-order absorption and absorption lag time. Body weight was a significant (P < 0.001) covariate of oral clearance of HCQ. The final model was assessed using GOF plots, a bootstrap, and visual predictive check, and this model was appropriate. Simulations based on the final model suggested that the recommended daily doses of HCQ sulfate (200-400 mg) based on the ideal body weight in Japanese patients with CLE/SLE were in the similar concentration ranges.
  
  
  CONCLUSIONS
  The PopPK models derived from both blood and plasma HCQ concentrations of Japanese patients with CLE/SLE were developed and validated. Based on this study, the dosage regimens of HCQ sulfate for Japanese patients with CLE/SLE should be calculated using the individual ideal body weight.
authors.affiliation: *Disposition, Safety and Animal Research; †Clinical Sciences, Clinical Sciences and Operations; and ‡Research and Development, Sanofi K.K., Tokyo, Japan.
authors.forename: Shigemichi
authors.initials: S
authors.lastname: Morita
authors.forename: Toshiya
authors.initials: T
authors.lastname: Takahashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yoshida
authors.forename: Naohisa
authors.initials: N
authors.lastname: Yokota
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D044466:Asian People; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D007564:Japan; D008178:Lupus Erythematosus, Cutaneous / Q000097:blood / Q000188:drug therapy*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D006886:Hydroxychloroquine