Pharmacokinetics of sotrastaurin combined with tacrolimus or mycophenolic acid in de novo kidney transplant recipients.

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.