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

• Published in: British journal of clinical pharmacology Vol. 61; no. 2; pp. 200 - 210
• Main Authors: Yeo, Kwee Poo, Lowe, Stephen L., Lim, Ming Tung, Voelker, James R., Burkey, Jennifer L., Wise, Stephen D.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-02-2006; Blackwell Science; Blackwell Science Inc
• Subjects: 6β‐hydroxycortisol; Adult; Biological and medical sciences; CYP3A4; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - drug effects; Cytochrome P-450 Enzyme System - physiology; Drug Interactions; enzyme induction; Enzyme Induction - drug effects; Enzyme Inhibitors - blood; Humans; Hydrocortisone - analogs & derivatives; Hydrocortisone - urine; Indoles - blood; Male; Maleimides - blood; Medical sciences; Pharmacology. Drug treatments; Protein Kinase C - antagonists & inhibitors; protein kinase C β; rifampicin; Rifampin - pharmacology; ruboxistaurin; 6β-hydroxycortisol; Protein kinase C; Enzyme; Induction; Isozyme; Toxicity; Transferases; Cytochrome P450; Enzyme inhibitor; Ruboxistaurin; CYP3A4; Antibiotic; Rifampicin; enzyme induction; Antituberculous agent; Antibacterial agent; Pharmacokinetics; protein kinase C β
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1111/j.1365-2125.2005.02540.x

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 Cmax and AUC(0,∞) of ruboxistaurin were significantly reduced by approximately 95% (P ≤ 0.001). For the metabolite, the mean Cmax decreased by 68% (P ≤ 0.001), and AUC(0,∞) decreased by 77% (P ≤ 0.001). The tmax 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.