CLINICAL PHARMACOLOGY & THERAPEUTICS VOLUME 73, NUMBER 2 American Society for Clinical Pharmacology and Therapeutics P 6 5

PIII-10 APPLICATION OF REAL-TIME DATA ASSEMBLY (RTDA)

TO A PIVOTAL PHASE III PEDIATRIC TRIAL: A PROACTIVE APPROACH TO POPULATION PHARMACOKINETIC/PHAR- MACODYNAMIC (PK/PD) DATASET CREATION. C. M. Ru- bino, PharmD, M. McPhee, MS, RN, M. Vo, PharmD, G. L. Jung- bluth, PhD, Cognigen Corporation, Pharmacia Coljporation, Buffalo, NY.

Purpose. To implement an RTDA process, similar to that de- scribed in the FDA Guidance for Industry: Population Pharmacoki- netics, during a Phase IIl trial of tinezolid (IV to oral) in pediatric patients which utilized an every 8 hour dosing regimen.

Methods. During study enrollment, data was transmitted monthly; data merges were performed to generate population PK-specific que- ries; queries were communicated for resolution. Descriptive figures and tables were provided to sponsor for internal discussions. The impact of the new dosing regimen on linezolid plasma concentrations was evaluated on a monthly basis as well. As it was not known at the start of the study how many patients would have PK samples drawn during administration of the oral suspension, this was monitored throughout the study in order to prospectively plan the analysis.

Results. Approximately 50 figures and queries were generated each month and over 100 data issues were resolved proactivety. The complicated process for merging of concentration data to CRF data was resolved prior to data lock, saving several weeks of dataset creation time.

Conclusions. Implementing RTDA improved data quality, re- duced data exclusions, and facilitated rapid dataset creation upon data lock. This process allowed early confirmation of the appropriateness of the new dosing regimen. Dataset creation issues were proactively resolved and the analysis was prospectively designed, allowing the population PK/PD analysis to be included in the FDA submission.

PIII-11 PHARMACOKINETICS OF SIBUTRAMINE IN HEALTHY

SUBJECTS UNDER FASTING AND FED CONDITIONS. Z~ Abolfathi, PhD, Francois Vallre, MSc and t~. Masson, PharmD, Div. of Scientific and Regulatory Affairs, Anapharm Member of SFBC International, Anapharm, Qurbec, Canada.

Sibutramine (S) is indicated for the management of obesity. S is metabolized in the liver to M1 (mono-desmethyl S) and M2 (di- desmethyl S). It exerts its pharmacological actions predominantly via these metabolites. The pharmacokinetics (PK) of S has not been adequately characterized. According to the monograph, food reduces M1 and M2 concentrations by 27% and 32% and delays the Tmax by 3h, but does not significantly affect their AUCs. Some safety con- cerns on S effects have been raised recently. This study was per- formed to provide more information about the PK of S and its metabolites under fasting and fed conditions. 6 healthy subjects were enrolled. Plasma conc. of S, M1 and M2 were determined by LC/ MS/MS method (LLOQ of 50 pg/mL). Non-compartmental pharma- cokinetic analyses were performed.

Table 1: Mean PK parameters under fasting conditions and ratio (Fed/Fast).

S M1 M2 (ratio fed/fast) (ratio fed/fast) (ratio ted/fast)

AUC0-t (pg.h/mL) 8709.53 (5) 29132.86 (2) 141912.53 (-) Cmax (pg/mL) 2984.92 (2 .5) 2138.93 (1.6) 7652.35 (-)

Contrarily to the monograph, this study showed that food signif- icantly increases bioavailability of S and M2, which could be impor- tant for the efficacy and safety of the drug.

PIII-12 INFLUENCE OF OMEPRAZOLE (O) ON THE BIOAVAIL-

ABILITY OF B1 FROM A SINGLE-TRIPLE (ST) CAPSULE OF BISMUTH BISKALCITRATE (BK) + TETRACYCLINE (T) + METRONIDAZOLE (M) FOR ERADICATION OF HELICOBAC- TER PYLORI. M. Lefebvre, PhD, C. Tremblay, BSc, C. Aumais, MD, J. Massicotte, BSc, J. Spenard, PhD, Algorithme Pharma Inc, Axcan Pharma, Mont Saint-Hilaire, Quebec, Canada.

Purpose O increases Bi bioavailability when given with colloidal Bi subcitrate. We tested if O also increases Bi bioavailability when given with the ST capsule containing BK. Methods 34 healthy volunteers completed the trial. Their mean (SD) age was 32 (7) y. They were randomized to one of 2 study groups add received 3 ST cap (each with BK 40 m g + T 125 mg + M 125 mg) QID Hone x 6 days or the same treatment + O 20 mg BID. Blood was drawn before the first dose on Days 4, 5 and 6, and a/so before the last dose on Day 7 and at .17, .25, .33, .5, .67, .84, 1, 1.33, 1.67, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 16, and 24 hours ,after. Plasma Bi levels were assayed by ICP/MS. Results Plasma Bi levels on Days 4, 5 and 6 showed that steady state was reached. After the last dose, mean (CV) Cmin were 2,882 pg/mL (36.3%) and 1,195 pg/mL (23.1%) (p<. 001) for treatment with O and without O respectively. Mean (CV) Cmax were 25,493 pg/mL (69.3%) and 8,061 pg/mL (28.1%) (p<. 001) for treatment with O and without O respectively. AUC 0-t increased by 2.9 in presence of O (p<.001). Adverse events reported were usually mild and of gastro-intestinal nature. Conclusions This study confirms an interaction between BK and O. Risk of Bi toxicity, seen after long term use of Bi compounds, is minimal here because plasma levels of Bi remained well below the toxic levels of 50 mcg/L and treatment period with this ST capsule + O is only of 10 days.

PIII-13 EFFECT OF PROBIOTICS AND COMMENSAL FLORA ON

HEAT SHOCK PROTEIN EXPRESSION AND NF-kB ACTIVITY IN GUT EPITHELIAL CELLS. E. O. Petrof, MD, K. Kojima, MD, M. W. Musch, PhD, C. De Simone, E. B. Chang, MD, University of Chicago, University of l'Aquila, Italy, Chicago, IL.

Colonic commensal flora is thought to play an important role in the development of Crohn's disease, and probiotics have been shown to improve the course of pouchitis and IBD in clinical trials. However, the mechanisms by which this occurs remain unclear. Our purpose was to elucidate the mechanisms underlying these beneficial micro- bial effects. Using western blot analysis, luciferase gene reporter assays and other molecular techniques, we found that the probiotic formulation VSL#3 and the enteric bacteria Bacteroides fragilis both induce the expression of inducible heat shock proteins and inhibit the pro-inflammatory NF-kB pathway in gut cpithelial cells. These ef- fects are mediated by soluble, heat-labile proteins produced by the bacteria. Cytoprotective and inducible heat shock proteins act as molecular chaperones to preserve vital cellular ftmctions when epi- thelial cells are exposed to a hostile insult or stress. NF-kB is a eukaryotic transcription factor known to play a cardinal role in the immune response to inflammation. The therapeutic effects of probi- otics and cytoprotective effects of commensal flora may be mediated through these mechanisms involving heat shock protein upregulation and blockade of the NF-kB pathway.