PI-15 THE EFFECT OF BOSENTAN ON ENDOTHELIAL FUNC- TION IN PATIENTS WITH CONGESTIVE HEART FAILURE. V. Dishy, MD, N. Uriel, MD, C. Stein, MD, A. Golik, MD, Z. Vered, MD, G. Cotter, MD, Dept of Medicine A, Assaf Harofe Medical Center, Cardiology Division, Assaf Harofe Medical Center, Division of Clinical Pharmacology, Vanderbilt University, Zerifin, Israel. BACKGROUND: Increased endothelin concentrations are one mechanism underlying endothelial dysfunction. Congestive heart failure (CHF) is characterized by increased levels of endothelin and endothelial dysfunction. Bosentan (BOS), a dual endothelin receptor blocker, have beneficial hemodynamic effects in patients with heart failure, but its effects on endothelial function are not known. METHODS: In a randomized, double blind, placebo controlled study we examined the effects of escalating doses of BOS (from 8mg to 240mg) on endothelial function in 22 patients with CHF (6 placebo, 16 BOS, 15 men, age: 712 years, ejection fraction: 291%). All patients were also treated with diuretics, beta-blockers and either ACE-inhibitors or angiotensin-receptor blockers. Endothe- lial function was assessed non-invasively at baseline and the last visit by measurement of central blood pressure and augmentation index using a semi-automated pulse wave analysis system. RESULTS: BOS resulted in a significant decrease in central systolic (-125 mmHg, p=0.03) and diastolic pressure (-123 mmHg, p=0.003) but augmentation index remained unchanged (from 273% at baseline to 243% after BOS, P=0.3). Time to reflection (a measure of pulse wave velocity) was unaffected by BOS treatment (from 1413 msec to 1444 msec, P=0.5). Placebo had no significant effect on any parameter. CONCLUSIONS: BOS, added to standard therapy for CHF, decreased blood pressure but had no effect on endothelial function. PI-16 QT INTERVAL ANALYSES FROM A PLACEBO AND POSI- TIVE CONTROLLED STUDY EVALUATING THE ELECTRO- PHYSIOLOGICAL EFFECTS OF DULOXETINE AT SUPRATH- ERAPEUTIC DOSES. L. Zhang, M. Derby, C. Gonzales, J. Chappell, R. Lucas, D. Small, M. P. Knadler, J. T. Callaghan, Eli Lilly, Indianapolis, IN. BACKGROUND/AIMS: The electrophysiological effects of du- loxetine at supratherapeutic exposures were evaluated to ensure com- pliance with regulatory criteria and to definitively establish the ab- sence of QT/QTc prolongation. METHODS: ECGs were collected in a multicenter, double blind, randomized, placebo-controlled, crossover study which enrolled 117 healthy female subjects aged 19 –74 years. Duloxetine dosages esca- lated from 60 mg BID to 200 mg BID; moxifloxacin 400 mg was a positive control. The primary analysis was of QTcF (Fridericia’s correction) based on a mixed-effect ANOVA model evaluated at the 200-mg BID level. Secondary analyses included a mixed-effect AN- COVA model with RR change from baseline as the covariate and an individual QT correction approach. RESULTS: Compared with placebo, the mean change from base- line in QTc decreased with duloxetine 200 mg BID. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs placebo were 0 msec at each time point by any correction method. Absolute QTcF values and the change in QTcF from baseline with duloxetine did not exceed 445 msec and 36 msec, respectively. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method. CONCLUSIONS: Duloxetine does not adversely affect ventric- ular repolarization as assessed by both mean changes and outliers in QT corrected by any correction method. PI-17 A DEFINITIVE QT STUDY INCORPORATING STEP-WISE DOSE ESCALATION TO STEADY-STATE. M. Derby, M. Gates, D. Small, J. T. Callaghan, Eli Lilly, Indianapolis, IN. BACKGROUND: Controversy exists surrounding the optimal study design to evaluate a drug’s effect on the QT interval. Con- founding issues include drug interactions, presence of metabolites, and tolerability at high dosages. These issues impacted a QT evalu- ation of duloxetine. METHODS: An initial study assessed the rate and feasibility of adaptive step-wise dose escalations to steady-state at supratherapeutic dosages and the linearity of the dose-exposure relationship. A second study measured exposures during maximal inhibition of drug metab- olism. ECGs were collected per ICH draft guidelines. RESULTS: The final design was a randomized, double-blind, placebo-controlled, two-way crossover study in healthy females, with a single dose of moxifloxacin as a positive control. Duloxetine was dosed per preliminary studies, which defined tolerability of a step- wise dosing scheme to exposures approximating those after maximal inhibition of 2D6 and 1A2 (5X the recommended dosage). Replicate ECGs were collected at baseline and compared with time-matched ECGs during placebo, duloxetine, and positive control periods at 4 separate times during the 12h-dosing interval. The primary endpoint was Fridericia’s corrected QT interval with a sample size to detect a 7.5 msec change from baseline due to drug. CONCLUSIONS: Tolerability issues and confounding pharma- codynamic factors can complicate study designs for QTc assessment. Preliminary studies can define limitations and maximize efficiency of study design. PI-18 EVALUATION OF DRUG INTERACTION DATA IN PRE- SCRIBING INFORMATION FOR NMES APPROVED IN 2000 – 2004. C. Collins, MD, H. Hachad, PharmD, I. Ragueneau, MD, R. Levy, PhD, University of Washington, Seattle, WA. BACKGROUND: The FDA released guidances for in vitro and in vivo drug metabolism/drug interaction studies in 1997 and 1999. This study was undertaken to evaluate the content of labeling information of 74 NMEs approved from 2000 to June 2004 for (i) drug metabo- lism/drug interaction data, (ii) the occurrence of labeling revisions for pharmacokinetic drug interactions and (iii) any gap between current labeling information and published literature. METHODS: Labeling information and reviews for NMEs (ex- cluding small molecules, ophthalmic solutions and topical com- pounds) was accessed at Drugs@FDA. RESULTS: Twenty agents (27%) did not include in vitro inhibi- tion data on their labeling. For these 20 agents, seven agents specif- ically stated that these studies were not performed, 2 agents included in vivo probe data on their labeling, 4 agents included the in vitro data in their review but did not place it in their labeling and for 7 agents, neither in vitro inhibition data or in vivo probe data were discussed in either the labeling or the released portion of their review. No agent was withdrawn for pharmacokinetic interactions. Seven agents (9%) underwent labeling revisions to supplement metabolic data or for pharmacokinetic interactions. Seven agents (9%) had potential inter- actions identified in the literature that were not addressed in current labeling information. CLINICAL PHARMACOLOGY & THERAPEUTICS P12 American Society for Clinical Pharmacology and Therapeutics FEBRUARY 2005