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Background: Ruboxistaurin, a specific inhibitor of the beta(1) and beta(2) isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route., Objective: To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522., Methods: Six healthy subjects (creatinine clearance >80 mL/min/1.73 m(2)) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32 mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis., Results: No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)], maximum plasma concentration [C(max)] and elimination half-life [t(1/2)]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p=0.163). Ruboxistaurin was well tolerated in both groups of subjects., Conclusion: These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.

Aim: To investigate the effect of duloxetine on the pharmacokinetics and tolerability of tolterodine and its active 5-hydroxymethyl metabolite (5-HM)., Methods: Sixteen healthy subjects received two 5-day treatment regimens in a randomized, double-blinded, crossover fashion: tolterodine (2 mg, BID) + duloxetine (40 mg, BID), tolterodine (2 mg, BID) + duloxetine placebo (BID). Plasma concentrations of tolterodine and 5-HM were measured on day 5. Adverse events, clinical safety laboratory data and vital signs were assessed during the study., Results: Duloxetine increased the AUC(tau,ss) of tolterodine by 71%[geometric mean, 95% confidence interval (CI) 31, 123], and its C(max,ss) by 64% (CI 30, 106), and prolonged its t(1/2) by 14% (CI 1, 28). Duloxetine did not affect the plasma concentrations or t(1/2) of 5-HM. Laboratory data and vital signs did not reveal any clinically significant changes or abnormalities., Conclusions: Duloxetine exhibited minor inhibitory effects on the pharmacokinetics of tolterodine but not 5-HM. Coadministration of these drugs was well tolerated and demonstrated no significant safety findings in the studied population. These findings suggest that there should not be a need for routine adjustment of tolterodine dosage in the presence of duloxetine.