PW-15

R. Boyd,1 W. Byon,1 J. Thompson,1 M. Johnson,1 J. Mandema2; 1Pfizer, Groton, CT, 2Quantitative Solutions Inc, Menlo Park, CA

Background: Model-Based Meta-Analyses can inform drug development decisions and increase the probability of technical success. Here we describe how the results of MBMA were used to support dose selection for the Phase II VTEtx study of apixaban (AMPLIFY).
Methods: Dose-response (D-R) MBMA of total VTE and major bleeding (MB) for anticoagulants in the prevention of VTE (VTEp) following orthopedic surgery were linked to efficacy (symptomatic VTE) and safety (MB) in VTEtx to generate D-R relationships across compounds, with doses expressed as enoxaparin equivalents. Separate relationships were determined for acute (5-14 days) and chronic (>14 days up to 6 months) effects of the initial treatment. Using these models, VTE and MB event frequencies for various dose regimens of apixaban were estimated.
Results: An apixaban regimen of 10 mg BID for 7 days followed by 5 mg BID was predicted to result in similar or better efficacy and safety vs. standard of care (enoxaparin + vitamin K antagonist) for the total treatment period (Table).
Conclusion:The MBMA supported selection of a dose of 10 mg BID for 7 days followed by 5 mg BID for the 6-month treatment of VTE. In AMPLIFY, this regimen of apixaban was noninferior for VTE and superior for MB, with observed relative risk (95% CI) of 0.84 (0.60-1.18) and 0.31 (0.17-0.55), respectively.

Model-Predicted Symptomatic VTE and MB Relative Risk [95% CI] for Apixaban Doses vs. Enoxaparin 1 mg/kg BID + Vitamin K Antagonist (VKA)
Treatment Acute Period Total Treatment Period
VTE MB VTE MB
1 mg/kg Enoxaparin BID + VKA 1 1 1 1
2.5 mg Apixaban BID 1.05
[0.93 - 1.2]
0.54
[0.43 - 0.68]
0.77
[0.56 - 1.06]
0.65
[ 0.43 - 1.0]
5 mg Apixaban BID 0.93
[0.8 - 1.08]
0.63
[0.49 - 0.82]
0.62
[0.41 - 0.93]
0.73
[0.51 - 1.06]
10 mg Apixaban BID 0.82
[0.67 - 1.01]
0.89
[0.57 - 1.38]
0.50
[0.31 - 0.81]
0.92
[0.53 - 1.58]
5 mg Apixaban BID x 7 days then 2.5 mg Apixaban BID 0.93
[0.80 - 1.08]
0.63
[0.49 - 0.82]
0.68
[0.49 - 0.94]
0.69
[0.46 - 1.05]
7.5 mg Apixaban BID x 7 days then 5 mg Apixaban BID 0.86
[0.72 - 1.03]
0.75
[0.54 - 1.05]
0.58
[0.38 - 0.87]
0.78
[0.54 - 1.13]
10 mg Apixaban BID x 7 days then 5 mg Apixaban BID 0.82
[0.67 - 1.01]
0.89
[0.57 - 1.38]
0.54
[0.36 - 0.83]
0.83
[0.57 - 1.22]
Note: 95% CI includes only model uncertainty and not sampling error