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

A Pharmacokinetic Drug
Interaction Study of Drug-72 and
Drug-12
Department of Mathematic & Statistics
York University
Yufeng Lin
Xiaofeng Zhou
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?
Assumption
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High tolerability
Moderate effect sizes
Different pharmacological profiles
Potentially different effects on outcomes.
Using α= 0.05 & β=80%
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 drug72 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 computergenerated 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 days=360 hours)
period2: May.17th---Aug.14th (90 days)
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.
| Period 1 | Washout | Period 2 |
---------------------------------------------------------72+placebo
------- >
72 + 12
72 + 12
------- >
72 +placebo
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-72+drug-12 at time 0 and drug-12 at
time 12 hours in every 24 hours period.
Group A:
drug-72+placebo
0h
Group A:
placebo only
12h
Group B:
drug-72+drug-12
Group B:
drug-12
In the period 2, reverse the treatment conditions
Group A:
drug-72+placebo
24h
Group B:
drug-72+drug-12
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
4h
6h
Blood draw 2
Blood draw 1
Total blood draws needed is 360 for each group
24h
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) >= 0
vs H1: C(6) – C(4) < 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.
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.