Potassium Chloride Modified Release Tablets Capsules 氯化钾缓释片与胶囊.ppt

KCl -- Documentation of BE... Potassium Chloride Tablets Capsules - Documentation of BE Advisory Committee for Pharmaceutical Sciences March 13, 2003 Barbara M. Davit, Ph.D. Deputy Director, Division of Bioequivalence Office of Generic Drugs CDER/FDA Discussion topics Design of potassium chloride BE studies Application of baseline correction to BE study data Impact of baseline correction on BE study outcome Comparison of two correction methods Draft Guidance for Industry Title and web address Potassium Chloride Modified-Release Tablets and Capsules: In vivo Bioequivalence and in Vitro Dissolution Testing /cder/guidance/4955dft.pdf Diet, fluid intake, climate conditions Urine collection for PK evaluation Data analysis Study design Controlled potassium intake of 50-60 mEq/day Normal potassium intake: 50-100 mEq/day Fluids according to schedule Single dose of 80 mEq potassium Sampling during 2 days before dosing to establish baseline Study design 2 Period, 2 Sequence, 2 Treatment Crossover Rationale for measuring potassium in urine Serum potassium is an insensitive measure Homeostatic mechanisms maintain serum potassium within narrow range normal range = 3.5-5 mEq/L Following a single dose of 80 mEq, serum potassium levels rise about 5% e.g., 4.3 mEq/L predosing; 4.55 mEq/L postdosing Data analysis Ae: amount excreted in each collection interval Ae0-24h, Ae0-48h: cumulative urinary excretion Rmax: maximal rate of excretion Tmax: time of maximal excretion Data analysis Both baseline-corrected uncorrected data are reported ANOVA and BE statistics are performed only on corrected data BE evaluation is on Ae0-24h, Rmax 90% CI for Test/Reference ratios must fall within 80 to 125% Baseline correction Subject and period specific Ae0-24h Correct by subtracting average Ae0-24h from the two baseline days Rmax Correct by subtracting baseline from corresponding interval Average of the two baseline day values Rationale for baseline correction Baseline reflects excretion