A Pharmacokinetic Drug Interaction Study of Drug-72 and Drug-12

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A Pharmacokinetic Drug Interaction Study of
Drug-72 and Drug-12

• Department of Mathematic Statistics
• York University
• Yufeng Lin
• Xiaofeng Zhou

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Problem

• Two drugs
• drug-72 with half-life time of 72 hours, taken
  once daily
• drug-12 with half-life time of 12 hours with
  potential interaction, taken twice daily
• Maximum concentration
• drug-72 alone is expected to be at 6 hours
• drug-72 and drug-12 together (interaction) is
  expected to be at 4 hours
• Question
• Is there an interaction between these two
  drugs?

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Assumption

• High tolerability
• Moderate effect sizes
• Different pharmacological profiles
• Potentially different effects on outcomes.
• Using a 0.05 ß80

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METHODS

• Subjects
• twenty-four normal, healthy adult male and female
  paid volunteers
• Method
• multiple dose within subjects, 2-way crossover
  design with double blind of drug-72 and drug-12
• all subjects will receive two treatment
  conditions during 180 days period.
• washout period 5 72 360 hours
• Study Procedures
• randomized assign 24 health adults into two
  groups A and B by a computer-generated code
• Medication combination
• Drug-72 placebo
• Drug-72 drug-12
• all subjects will be dosed with each medication
  combination start from Feb 1st midnight
• period1 Feb.1st---May.1st (90 days)
• washout period May.2nd---May.16th (15
  days360 hours)
• period2 May.17th---Aug.14th (90 days)

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Continue.

• Study Procedures
• randomized assigned each group to one of the drug
  combinations
• every 24 hours are a small time interval for a
  180 days treatment condition
• in every 24 hours period, Treatment conditions
  were
• Group A, take drug-72 and placebo (1 capsulate
  for each) and group B, take drug-72 and drug-12
  (1 capsulate) on midnight
• Every 12 hours, group 1, take placebo (1
  capsulate) and group 2, take drug-12 (1
  capsulate).
• Repeated until 180 days period reached.

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• Period 1 Washout Period 2
  
• -------------------------------------------------
  ---------
• 72placebo ------- gt 72 12
• 72 12 ------- gt 72
  placebo

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• In period 1, group A take drug-72 placebo at
  time 0 and placebo only at time 12 hours in every
  24 hours period, group B take drug-72drug-12 at
  time 0 and drug-12 at time 12 hours in every 24
  hours period.

Group A drug-72placebo
Group A drug-72placebo
Group A placebo only
0h
24h
12h
Group B drug-72drug-12
Group B drug-12
Group B drug-72drug-12
In the period 2, reverse the treatment conditions
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• In every 24 hours period, for each group
  we do blood draw two times, and record c(4) and
  c(6).
• c(4) blood concentration at 4 hours
• c(6) blood concentration at 6 hours

0h
24h
4h
6h
Blood draw 2
Blood draw 1
Total blood draws needed is 360 for each group
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Statistical Analyses

• primary endpoint in the study is Cmax (maximum
  blood concentration).
• during first period, for each group, do
  hypotheses test
• H0 C(6) C(4) gt 0
• vs H1 C(6) C(4) lt 0
• then for the group, if H0 is true, we can tell
  that the group patients have taken the drug-72
  and placebo, while if H0 is reject, then that
  group patients have taken the drug-72 and drug-12
  because the maximum concentration is at 4 hours
  when interaction occurs.
• If in period 1 we get H0 is true and in period 2
  H1 is true for the same group, then it
  approximately shows the evidence that the
  interaction effect has occur.

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Some explanation

• The washout period
• Using minimum duration of 5 times the half-life
  of the treatment
• i.e. 72 5 360 hours 15 days.
• We need 360 blood draws during the 180 days
  trial.
• (Since during every 24 hours, we need do two
  blood draws on 4 hours and 6 hours, and total we
  have 180 days, so we need 2 180 360)
• We use double-blind to keep both subjects and
  investigators are unware of treatment assignment
• If patients drop out during the study, we still
  keep their records and do analysis, but
  additional analysis will be perform only using
  the data collected from the patients who complete
  the trial.