title: Pharmacokinetics of everolimus when combined with cyclosporine in Japanese de novo renal transplant recipients.
abstract: BACKGROUND
  Currently, there are no published data on pharmacokinetics (PK) of everolimus in combination with cyclosporine in Japanese renal transplant patients. We evaluated the PK of everolimus in Japanese de novo renal transplant patients who received everolimus in combination with cyclosporine.
  
  
  METHODS
  In this phase 3, multicenter, randomized, open-label study, patients were randomized (1:1) to 1 of the 2 groups: everolimus 1.5 mg (targeted C0 of 3-8 ng/mL) plus reduced-dose cyclosporine or mycophenolate mofetil 2 g/d plus standard-dose cyclosporine. PK assessments for everolimus were performed on day 28 (month 1) in the PK subpopulation.
  
  
  RESULTS
  A total of 11 patients (7 men), mean age 47.5 ± 11.21 years, were enrolled for PK analysis of everolimus. Starting at 1.5 mg (0.75 mg twice a day), the mean dose over a period of 28 days was 0.705 ± 0.1011 mg. Everolimus mean trough concentration was 4.307 ± 1.2459 ng/mL and mean peak concentration was 13.539 ± 3.5330 ng/mL, which peaked at 1 to 2 hours postdose. The average concentration was 7.558 ± 1.4723 ng/mL, area under the concentration-time curve was 90.70 ± 17.667 ng·h/mL, and peak-trough fluctuation was 122.6%. The PK parameters of everolimus were comparable to those in the earlier phase 3 studies (A2306 and A2307). The mean everolimus trough levels were within the target ranges at all time points ranging from 3.4 to 5.5 ng/mL (everolimus 0.75 mg twice a day, safety population). The majority of patients (>85% from day 7 onward) were maintained within the targeted everolimus trough blood levels (safety population). These data were similar to a non-Japanese study (A2309).
  
  
  CONCLUSIONS
  The pharmacokinetic characteristics of everolimus in Japanese de novo renal transplant patients did not differ from those previously observed in non-Japanese patients, hence the same dosage of everolimus may be acceptable in Japanese patients.
authors.affiliation: Department of Organ Transplant Surgery, Aichi Medical University, Nagakute, Aichi, Japan. Electronic address: kaz-uchida@minos.ocn.ne.jp.
authors.forename: K
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Department of Urology, Fujita Health University School of Medicine, Kutsukake-cho, Toyoake, Aichi, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Hoshinaga
authors.affiliation: Department of Organ Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Aichi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Watarai
authors.affiliation: Department of Organ Transplant Surgery, Nagoya Daini Red Cross Hospital, Nagoya, Aichi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Goto
authors.affiliation: Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kusaka
authors.affiliation: Department of Urology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Translational Sciences Department, Development Division, Novartis Pharma K.K. 106-8618, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hirano
mesh_terms: D000328:Adult; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage*; D004359:Drug Therapy, Combination; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007564:Japan; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000068338:Everolimus; D020123:Sirolimus