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

• Diet, fluid intake, climate conditions
• Urine collection for PK evaluation
• Data analysis
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KCl -- Documentation of BE...
Study design
• Controlled potassium intake of 50-60 mEq/day
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Study design
2 Period, 2 Sequence, 2 Treatment Crossover
Dose in AM, Day 7
Days 1-4: diet equilibration
Days 5-6: measure baseline
Office of Generic Drugs CDER/FDA
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
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KCl -- Documentation of BE...
Draft Guidance for Industry
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
1.09
0.92 1.12 0.93 1.14 0.95 1.23
All baseline corrections were specific to subject and period
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Conclusions
• Baseline correction is essential for evaluating BE of potassium chloride tablets
• To compare amounts of drug delivered from two formulations, must correct for amount excreted due to food
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Baseline excretion rate data
– e.g., 4.3 mEq/L predosing; 4.55 mEq/L postdosing
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Kห้องสมุดไป่ตู้l -- Documentation of BE...
Data analysis
• Ae: amount excreted in each collection interval
90% Confidence Interval
Correction Point estimate
method used
Lower
Upper
Corrected for baseline
1.04
0.93
1.14
No baseline correction
1.00
0.95
1.06
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– 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
Excretion rate, mEq/hour
8 6 4 2 0
0
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pre-dose, test pre-dose, reference post-dose, test post-dose, reference
4
8
12
16
20
24
Midpoint of collection interval, hours
Days 7-8: post-dosing
Each study period = 8 days in duration
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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%
• Title and web address
– Potassium Chloride Modified-Release Tablets and Capsules: In vivo Bioequivalence and in Vitro Dissolution Testing
– /cder/guidance/4955dft.pdf
Formulation B, Rmax, 90% CIs
Baseline Correction Point
90% CI
Method Used
Estimate Low Hi
Uncorrected
1.01
Subtract mean baseline from 2 baseline days
1.02
Subtract mean baseline, corresponding interval
• 90% CI for Test/Reference ratios must fall within 80 to 125%
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KCl -- Documentation of BE...
Baseline correction
• Subject and period specific
• Ae0-24h, Ae0-48h: cumulative urinary excretion
• Rmax: maximal rate of excretion • Tmax: time of maximal excretion
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KCl -- Documentation of BE...
Excretion rate, mEq/hour
8
Arrows indicate meal times
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4
Test, Period 1 Ref, Period 1 Test, Period 2 Ref, Period 2
2
0
0
4
8
12
16
20
24
Midpoint of collection interval, hours
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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
– All parameters met 90% CI criteria
• Application found acceptable
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KCl -- Documentation of BE...
Formulation B, Ae0-24h, 90% CIs
• 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
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KCl -- Documentation of BE...
Rationale for baseline correction
• Baseline reflects excretion of potassium provided in food