Willem De Winter (1), Dave Polidori (2), Eef Hoeben (1), Damayanthi Devineni (3), Martine Neyens (1), An Vermeulen (1)
(1) Janssen Research and Development, Turnhoutseweg 30, Beerse, Belgium, (2) Janssen Research and Development, LLC, 3210 Merryfield Row, San Diego, CA, USA, (3) 920 Route 202, Raritan, NJ, USA
Objectives: Canagliflozin is an orally active inhibitor of SGLT2, currently in development for the treatment of patients with T2DM. A population PK/PD analysis is presented which identifies the canagliflozin plasma exposure-response relationship on HbA1c in subjects with T2DM, and integrates this with a previously identified relationship between plasma canagliflozin exposure and reduction in renal threshold for glucose excretion (RTG) [1].
Methods: A mathematical model relating exposure of canagliflozin to reductions in HbA1c was developed using observed relationships between canagliflozin exposure and the effect of canagliflozin on RTG, observed relationships between changes in RTG and mean plasma glucose (MPG), and known relationships between MPG and HbA1c. The model was implemented as a population PK/PD model in NONMEM 7.1 using observed HbA1c responses and estimated individual canagliflozin plasma exposures from 1445 subjects with T2DM from four pooled studies: a 12-week Phase 2b study (N=352) and three 26-week Phase 3 studies (N=1093, including 249 subjects from a dedicated study in patients with moderate renal impairment). Covariate effects were evaluated for age, body weight, BMI, sex, race and estimated glomerular filtration rate (eGFR).
Results: The population PK/PD model provided a satisfactory fit to the observed data. The effects of placebo (including diet and exercise) and canagliflozin were found to be dependent on baseline HbA1c. The model included an Emax that increased with increasing baseline HbA1c and increasing eGFR, with a value of -0.73% obtained for a typical subject with baseline HbA1c of 7.77% and baseline eGFR of 90 ml/min/1.73m2. A significant covariate effect was identified only for eGFR on Emax. In addition to the exposure-dependent reductions in HbA1c attributable to decreases in RTG, an additional HbA1c-lowering effect of canagliflozin 300 mg compared to canagliflozin 100 mg of -0.15% was identified, which was additive to the effect described by the Emax model.
Conclusions: A significant covariate effect of eGFR was identified on the maximum HbA1c-lowering effect of canagliflozin (Emax), which is consistent with the renal mechanism of action of canagliflozin. An additional HbA1c-lowering effect for the 300 mg dose strength on top of the HbA1c-lowering effect of canagliflozin attributable to RTG-lowering, is consistent with a potential secondary effect of the 300 mg dose to delay intestinal glucose absorption [2].
References:
[1] Sha S, Devineni D, Ghosh A, Polidori D, Chien S, Wexler D, Shalayda K, Demarest K, Rothenberg P (2011). Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes Metab. 13(7):669-72.
[2] Polidori D, Sha S, Mudaliar S, Ciaraldi TP, Ghosh A, Vaccaro N, Farrell K, Rothenberg P, Henry RR (2011). Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion. Results of a randomized, placebo-controlled study. Diabetes Care, February 14, 2013, doi:10.2337/dc12-2391.
Reference: PAGE 22 (2013) Abstr 2872 [www.page-meeting.org/?abstract=2872]
Poster: Other Drug/Disease Modelling