Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin‐mediated CYP3A4 induction

Aims

The aim of this study was to evaluate the effect of rifampicin co‐administration on the pharmacokinetics of ruboxistaurin and its active metabolite, N‐desmethyl ruboxistaurin and, in addition, to compare the changes in pharmacokinetics of ruboxistaurin and N‐desmethyl ruboxistaurin with the urinary 6β‐hydroxycortisol : cortisol ratio. Ruboxistaurin is a specific protein‐kinase‐C β inhibitor in clinical development for the treatment of diabetic microvascular complications.

Methods

This was a two‐period, one‐sequence study. Sixteen healthy male subjects completed both study periods. In period one, a single 64 mg oral dose of ruboxistaurin was administered. In period two, 600 mg rifampicin was administered daily for 9 days, during which another single 64 mg ruboxistaurin dose was administered on day 7. Blood samples were collected and assayed for ruboxistaurin and N‐desmethyl ruboxistaurin. CYP3A4 induction was assessed by ratios of urinary 6β‐hydroxycortisol : cortisol (6β‐OHC : C) obtained via 24 h and morning‐spot sampling techniques.

Results

Following repeated doses of rifampicin, both the mean C_max and AUC(0,∞) of ruboxistaurin were significantly reduced by approximately 95% (P ≤ 0.001). For the metabolite, the mean C_max decreased by 68% (P ≤ 0.001), and AUC(0,∞) decreased by 77% (P ≤ 0.001). The t_max values did not appear affected. The 6β‐OHC : C ratios from both 24 h and morning spot methods increased significantly, consistent with CYP3A4 induction.

Conclusions

The effect of rifampicin co‐administration on the exposure of ruboxistaurin is consistent with ruboxistaurin being a substrate of CYP3A4. Therefore, co‐administration with known CYP3A4 inducing agents (rifampicin, carbamazepine, phenobarbital, etc.) may decrease the concentrations of ruboxistaurin and N‐desmethyl‐ruboxistaurin. In this study, 6β OHC : C ratios substantially underestimated the impact of rifampicin on ruboxistaurin.

DOI: 10.1111/j.1365-2125.2005.02540.x

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