The effect on sotrastaurin pharmacokinetics of strong CYP3A inhibition by ketoconazole

center dot Sotrastaurin is an investigational protein kinase C inhibitor. This represents a new mechanism of action for immunosuppression to prevent acute rejection after organ transplantation. In vitro experiments indicate that sotrastaurin is a substrate of CYP3A4. WHAT THIS STUDY ADDS center dot This study provides clinical pharmacokinetic information to quantify the effect of the strong CYP3A4 inhibitor ketoconazole on sotrastaurin. The susceptibility of sotrastaurin to CYP3A4-related drug interactions is placed in the context of similar information about calcineurin inhibitors (tacrolimus, ciclosporin) and T-cell proliferation inhibitors (everolimus, sirolimus). AIMS Sotrastaurin is an immunosuppressant that reduces T-lymphocyte activation via protein kinase C inhibition. The effect of CYP3A4 inhibition by ketoconazole on the pharmacokinetics of sotrastaurin, a CYP3A4 substrate, was investigated. METHODS This was a two-period, single-sequence crossover study in 18 healthy subjects. They received a single 50 mg oral dose of sotrastaurin in period 1 followed by a 14-day inter-treatment phase. In period 2 they received ketoconazole 200 mg twice daily for 6 days and a single 50 mg dose of sotrastaurin on the fourth day of ketoconazole administration. RESULTS Co-administration of single-dose sotrastaurin during steady-state ketoconazole increased sotrastaurin C(max) by 2.5-fold (90% confidence interval 2.2, 2.9) from 285 +/- 128 to 678 +/- 189 ng ml(-1) and increased AUC by 4.6-fold (4.1, 5.2) from 1666 +/- 808 to 7378 +/- 3011 ng ml(-1) h. Sotrastaurin half-life was nearly doubled from 5.9 +/- 1.7 to 10.6 +/- 2.5 h. The AUC of the active metabolite N-desmethyl-sotrastaurin was increased by 6.8-fold. Sotrastaurin did not alter ketoconazole steady-state predose plasma concentrations. CONCLUSIONS The strong CYP3A4 inhibitor ketoconazole increased sotrastaurin AUC by 4.6-fold. A compensatory reduction in the dose of sotrastaurin is warranted when strong CYP3A4 inhibitors are co-administered.