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