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Potassium Chloride Tablets & Capsules - 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

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Potassium Chloride Tablets & Capsules - Documentation of BE

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  1. 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

  2. KCl -- Documentation of BE... 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

  3. KCl -- Documentation of BE... Draft Guidance for Industry • Title and web address • Potassium Chloride Modified-Release Tablets and Capsules: In vivo Bioequivalence and in Vitro Dissolution Testing • http://www.fda.gov/cder/guidance/4955dft.pdf • Diet, fluid intake, climate conditions • Urine collection for PK evaluation • Data analysis

  4. KCl -- Documentation of BE... 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

  5. KCl -- Documentation of BE... Study design 2 Period, 2 Sequence, 2 Treatment Crossover Dose in AM, Day 7 Days 5-6: measure baseline Days 7-8: post-dosing Days 1-4: diet equilibration Each study period = 8 days in duration

  6. KCl -- Documentation of BE... 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

  7. KCl -- Documentation of BE... 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

  8. KCl -- Documentation of BE... 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%

  9. KCl -- Documentation of BE... 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

  10. KCl -- Documentation of BE... Rationale for baseline correction • Baseline reflects excretion of potassium provided in food • Amount excreted following dosing arises from the dose and food intake • To compare amounts of drug delivered from two formulations, must correct for amount excreted due to food

  11. KCl -- Documentation of BE... Baseline excretion rate data Arrows indicate meal times

  12. KCl -- Documentation of BE... Case study: Formulation A • 20 mEq extended-release tablet • ANOVA without baseline adjustment • All parameters met 90% CI criteria • ANOVA with baseline adjustment • Rmax did not meet 90% CI criteria • Application found unacceptable

  13. KCl -- Documentation of BE... Formulation A, Ae0-24h, 90% CIs

  14. KCl -- Documentation of BE... Formulation A, Rmax, 90% CIs

  15. KCl -- Documentation of BE... Excretion rate, uncorrected

  16. KCl -- Documentation of BE... Excretion rate, corrected

  17. KCl -- Documentation of BE... Case study, Formulation B • 20 mEq extended-release tablet • ANOVA without baseline adjustment • All parameters met 90% CI criteria • ANOVA with baseline adjustment • All parameters met 90% CI criteria • Application found acceptable

  18. KCl -- Documentation of BE... Formulation B, Ae0-24h, 90% CIs

  19. KCl -- Documentation of BE... Formulation B, Rmax, 90% CIs

  20. KCl -- Documentation of BE... Conclusions • Baseline correction is essential for evaluating BE of potassium chloride tablets • The baseline is reproducible during the equilibration periods • Baseline-corrected data are more sensitive to changes in formulation performance • Study outcome was the same with either of two proposed correction methods

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