A. Marathe,1 R. Jain,1 L. Jain,1 C. Hsu,2 J. Pinheiro,2 W. D. Winter,2 C. G. Sahajwalla,1 V. Sinha,1 N. Mehrotra1; 1Office of Clinical Pharmacology, OTS, CDER, Food and Drug Administration, Silver Spring, MD, 2Model Based Drug Development, Janssen Research and Development, LLC, Raritan, NJ
BACKGROUND: Canagliflozin is approved as a once-daily (QD) dosing regimen for type 2 diabetes. The applicant developed a fixed dose combination (FDC) with metformin for twice-daily (BID) administration. Efficacy and safety for the FDC were supported by Phase III trials evaluating canagliflozin QD and a Phase II trial evaluating canagliflozin BID on a background of metformin against metformin placebo. The Phase II efficacy trial did not include the corresponding QD regimen as comparator and a cross-trial comparison showed lower placebo-subtracted change from baseline in HbA1c for BID vs. QD regimens. The Agency recommended the applicant to utilize exposure response analysis to bridge the efficacy of QD and BID FDC regimens in lieu of conducting an additional clinical trial.
METHODS: A modeling and simulation strategy was discussed between the Agency and the applicant with the Agency outlining the key expectations of a model based approach. Based on the Agency’s recommendation, a dynamic population PK/PD model linking time profiles of canagliflozin plasma concentrations to time profiles of HbA1c was developed by the applicant. External validation of population PK and PK/PD models, and sensitivity analyses were incorporated in a detailed plan. Simulations were conducted to predict the HbA1c profiles for both regimens under similar demographics and baseline conditions.
RESULTS: Simulations demonstrated that the differences in HbA1c reduction between the BID and QD regimens in patients with similar baseline conditions and total daily doses were small (at most 0.03% at week 26) and clinically assessed as not meaningful.
CONCLUSION: Modeling and simulation supported the regulatory approval of the FDC by bridging efficacy between the QD and BID regimens and avoided the need for an additional clinical trial.