Pharmacokinetics of Sotrastaurin Combined With Tacrolimus or Mycophenolic Acid in De Novo Kidney Transplant Recipients
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Kovarik, John M. (2011) Pharmacokinetics of Sotrastaurin Combined With Tacrolimus or Mycophenolic Acid in De Novo Kidney Transplant Recipients. Transplantation, 91 (3). pp. 317-322. ISSN 0041-1337
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, n74), 200 mg sotrastaurin twice daily with standardexposure
tacrolimus (treatment B, n76), or 200 mg sotrastaurin twice daily with reduced-exposure tacrolimus
(treatment C, n66). 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 0.60.4 g/mL and did not differ when combined with
standard-exposure versus reduced-exposure tacrolimus (P0.99) nor when tacrolimus was replaced by MPA
(P0.11). Sotrastaurin peak concentration was 1.60.6 g/mL, and area under the drug concentration-time curve
over a dosing interval (AUC) was 12.24.2 g 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 (r20.62, P0.0001). 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.
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| Date Deposited: | 13 Oct 2015 13:15 |
| Last Modified: | 13 Oct 2015 13:15 |
| URI: | https://oak.novartis.com/id/eprint/4734 |