title: Pharmacokinetics of sotrastaurin combined with tacrolimus or mycophenolic acid in de novo kidney transplant recipients.
abstract: BACKGROUND
  Sotrastaurin is a protein kinase C inhibitor in the development for prevention of organ rejection after renal transplantation.
  
  
  METHODS
  In a multicenter phase 2 trial, 216 de novo renal transplant recipients were randomized to mycophenolic acid (MPA) with standard-exposure tacrolimus (treatment A, n=74), 200 mg sotrastaurin twice daily with standard-exposure tacrolimus (treatment B, n=76), or 200 mg sotrastaurin twice daily with reduced-exposure tacrolimus (treatment C, n=66). After month 3, tacrolimus was replaced with MPA in arms B and C. The longitudinal pharmacokinetics of sotrastaurin and tacrolimus were prospectively evaluated through month 6.
  
  
  RESULTS
  Sotrastaurin predose drug concentration (C0) was 0.6±0.4 μg/mL and did not differ when combined with standard-exposure versus reduced-exposure tacrolimus (P=0.99) nor when tacrolimus was replaced by MPA (P=0.11). Sotrastaurin peak concentration was 1.6±0.6 μg/mL, and area under the drug concentration-time curve over a dosing interval (AUC) was 12.2±4.2 μg hr/mL. Intersubject variability in AUC was 27% and not significantly influenced by age (18-67 years), weight (47-121 kg), sex, or creatinine clearance (36-173 mL/min). Sotrastaurin C0 was positively correlated with AUC (r=0.62, P<0.0001). Sotrastaurin increased tacrolimus concentrations by a pharmacokinetic interaction inasmuch as the tacrolimus dose needed to achieve a given C0 was up to 47% lower when combined with sotrastaurin versus with MPA.
  
  
  CONCLUSIONS
  Sotrastaurin pharmacokinetics were similar when combined with reduced-exposure or standard-exposure tacrolimus or with MPA. Tacrolimus exposure was significantly increased by sotrastaurin in the initial weeks posttransplant by a pharmacokinetic interaction.
authors.affiliation: Clinical Pharmacology and Clinical Research, Novartis Pharmaceuticals, Basel, Switzerland. john.kovarik@novartis.com
authors.forename: John M
authors.initials: JM
authors.lastname: Kovarik
authors.forename: Jürg U
authors.initials: JU
authors.lastname: Steiger
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyo
authors.forename: Lionel
authors.initials: L
authors.lastname: Rostaing
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Arns
authors.forename: Jacques
authors.initials: J
authors.lastname: Dantal
authors.forename: Pieter
authors.initials: P
authors.lastname: Proot
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use; D016030:Kidney Transplantation; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D011758:Pyrroles; D011799:Quinazolines; C543528:sotrastaurin; D009173:Mycophenolic Acid; D016559:Tacrolimus