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12th International Workshop on Clinical Pharmacology of HIV TherapyApril 13-15, 2011, Miami, FL
Using Adaptive/Bayesian Methodology to Evaluate Four Different Formulations of GSK2248761 in a Relative Bioavailability and Food Effect Study (SGN113391)
Yu Lou*, Shuguang Chen, Elizabeth Gould, Amanda Peppercorn, Joseph Kim, Stephen PiscitelliGlaxoSmithKline, RTP, USA
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Background
SGN113391 (Idenix899, GSK2248761) • Relative Bioavailability Study
– The original Gelucire capsule formulation required refrigeration, was not scalable for large trials and demonstrated a food effect
– 5 new formulations considered• 2 wet granulated
– milled and micronized drug substance
• Wet bead milled capsule• Wax granulated tablet• Hot melt extrude formulation
– 2 formulations did not meet manufacturing criteria– 3 other formulations were selected
Poster P6: GSK2248761 Development, Formulation, and Food Effect
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Challenges and Goals
• Select a formulation to replace the Gelucire capsule prior to initiation of Phase IIb study
• Study the food effect• Consideration of PK variability• Efficient study conduct
– Time– Subjects enrolled– Reduced dropout rate
Result: confident formulation selection
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Study Design Options
• 3 design options considered– 7 period single dose balanced crossover
• 3 test formulations with/without food and 1 reference treatment with food
– 5 period single dose crossover (for two new formulations) and additional 2 periods for 3rd formulation
• 2 test formulation with/without food and 1 reference treatment with food• Plus 3rd formulation with/without food
– Two of 3x3 period crossover and optional to have additional 2 periods (adaptive design)
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Adaptive Study Design Selected
Cohort 1: treatments A, B, C
Cohort 2: treatments A, D, E
Subjects from Cohorts 1&2: F/G
Treatment A: Gelucire formulation/with food (reference)
Treatments B/C: 1st formulation with or without food
Treatments D/E: 2nd formulation with or without food
Treatments F/G: 3rd formulation with or without food
Part A Part B
Evaluation &Decision
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Endpoint Considerations
• Endpoint: R = test/reference, the ratio of the geometric least square mean (GLSmean) of PK parameters of test treatment vs reference treatment
• Evaluation criteria:– 90% CI: (0.8-1.25) or (0.7-1.43)
• Not chosen as required large sample size– R >0.8 or R >0.9 for the point estimate
• Chosen when small sample size
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Bayesian Method Simulation
• 200 trials were simulated with n=10, CV% at 30%, and true R =0.8
• Calculate the GLSmean ratio R for each simulated trial
• Calculate the predictive probability of R >0.8 with WinbugsTM
Predictive Probability Mean and range of R from the 200 trials
Prob (R >0.8) >50% 0.88 (0.80 - 1.06) Prob (R >0.8) 50% 0.72 (0.60 - 0.79)
WinBUGS -- a Bayesian modelling framework: concepts, structure, and extensibility, Lunn, D.J., Thomas, A., Best, N., and Spiegelhalter, D. (2000)
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Decision Rule Selection
0,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
80,0
90,0
100,0
CV%=30 CV%=70 CV%=30 CV%=70
N=10, true ratio=1 N=10, true ratio=0.8
Prob(r>0.8)>50%Prob(r>0.8)>70%Geomean ratio >0.8
Factors influencing the ru1. True ratio2. Cut point, limit3. Confidence level4. Variability
Prob
abili
ty to
Mee
t the
Crit
eria
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Results: Individual Subject’s Ratios vs Distribution
Histogram of Posterior Probability of B vs A Ratio
Test/Reference Ratio
Freq
uenc
y
0.0 0.5 1.0 1.5 2.0
020
040
060
080
0
Individual subject’s ratio
A= Gelucire referenceB= 1st formulation without food
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Results: Individual Subject’s Ratio vs Distribution
Histogram of Posterior Probability of D vs A Ratio
Test/Reference Ratio
Freq
uenc
y
0 1 2 3 4
020
040
060
0
Individual Subject’s Ratio
A= Gelucire referenceD= 2nd formulation without food
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Summary
• Traditional (0.8 -1.25) region for 90% CI of GLSmean ratio requires much larger sample size and/or lower variability
• Posterior probability of (R>r)>50% and traditional GLSmean ratio greater than a cut point (r) gave almost the same results
• Posterior distribution of treatment ratio provided additional information on variability which is important when sample size is small
• Prob (R>r)>50% is more like the median and is more robust than the mean when there are outliers
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL
Summary
• Using adaptive designs and Bayesian decision criteria– Decision rules can be setup before seeing data,
enabling quick decision making, reducing unnecessary dosing periods and lowering costs
– Applicable for drug-drug interaction studies
12th International Workshop on Clinical Pharmacology of HIV Therapy, April 13-15, 2011, Miami, FL