Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin-mediated CYP3A4 induction.
OBJECTIVE
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 6beta-hydroxycortisol : cortisol ratio. Ruboxistaurin is a specific protein-kinase-C beta 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 6beta-hydroxycortisol : cortisol (6beta-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,infinity) of ruboxistaurin were significantly reduced by approximately 95% (P < or = 0.001). For the metabolite, the mean C(max) decreased by 68% (P < or = 0.001), and AUC(0,infinity) decreased by 77% (P < or = 0.001). The t(max) values did not appear affected. The 6beta-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, 6beta OHC : C ratios substantially underestimated the impact of rifampicin on ruboxistaurin.
Yeo
Kwee Poo
KP
Lilly-NUS Centre for Clinical Pharmacology, National University of Singapore, Singapore.
Lowe
Stephen L
SL
Lim
Ming Tung
MT
Voelker
James R
JR
Burkey
Jennifer L
JL
Wise
Stephen D
SD
D000328:Adult; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000097:blood*; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives / Q000652:urine; D007211:Indoles / Q000097:blood*; D008297:Male; D008301:Maleimides / Q000097:blood*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D012293:Rifampin / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C001380:6 beta-hydroxycortisol; C099154:ruboxistaurin; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011493:Protein Kinase C; D012293:Rifampin; D006854:Hydrocortisone