2011 - Athens - Greece

PAGE 2011: Other topics - Applications
Candice Jamois

Title Pharmacokinetic-Pharmacodynamic Modeling of the Relationship between Aleglitazar Exposure and Lipids Response in Type 2 Diabetes Patients.

Candice Jamois1, Nicolas Frey1, Matthias Herz2

(1) Modeling and Simulation group, Pharma Research and Early Development, Translational Research Sciences, F.Hoffmann-La Roche AG, Basel, Switzerland. (2) Pharma Development, Metabolism, F.Hoffmann-La Roche AG, Basel, Switzerland.

Objectives: To develop population pharmacokinetic-pharmacodynamic (PK-PD) models describing the relationships between selected efficacy parameters, TG, HDL-C and LDL-C and aleglitazar exposure in patients with T2DM.

Methods: Data from SYNCHRONY, a 16-week phase 2 dose-ranging study which evaluated 4 doses of aleglitazar (50, 150, 300 and 600 mg), were used to investigate the relationship between aleglitazar exposure at steady state (SS) and the subsequent lipid response. Non linear mixed effect approaches, using NONMEM, were used to characterize the pharmacokinetic (PK) and the exposure-response relationships (PK-PD) of aleglitazar. TG, HDL-C and LDL-C response were analyzed separately and related to aleglitazar exposure at steady-state (AUC). Emax and power models were tested to describe the relationships between aleglitazar exposure and TG, HDL-C and LDL-C. Effect compartments were used to describe the link between PK and lipids parameters. Simulations were performed to evaluate the predictive performance of the PK-PD models and to illustrate in a large population of T2DM patients the expected lipids response at SS.

Results: Plasma concentrations of aleglitazar over time were accurately described by a two-compartment disposition PK model with first-order absorption and first-order elimination. Significant Emax relationships were established between the AUC of aleglitazar at SS and the decrease observed in LDL-C and TG in SYNCHRONY, while a power model adequately described the relationship between AUC and HDL-C increase. The effect mean equilibration half-life was 18.7, 4.1, and 8.7 days for HDL-C, LDL-C and TG respectively. The steady-state of the effect was reached in approximately 13, 3 and 6 weeks for HDL-C, LDL-C and TG respectively. At steady-state, the respective TG and LDL-C mean decrease from baseline were estimated to 81 and 49%. The slope parameter was estimated to 1.9 10-2 day2 for HDL-C. Visual predictive checks have confirmed the good predictive qualities of these models. Subsequently, the three exposure-response models were used to explore the response at SS in a large population of 1000 patients.

Conclusion: Population PK-PD analyses confirmed the clinical efficacy of aleglitazar on dyslipidemia in T2DM patients. The effects of these population PK-PD parameters will be evaluated in an ongoing prospective cardiovascular outcome study to assess the impact of improvements in lipid parameters on reducing the cardiovascular sequelae of T2DM.

 

References
[1]. WHO. Diabetes. Fact sheet N0 312. Geneva: World Health Organization, 2008.
[2]. American Diabetes Association. Standard of medical care in diabetes-2008. Diabetes Care 2008; 31 (suppl 1):S12-54.
[3]. Graham I, Atar D, Borch-Johnsen K, et al. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J 2007; 28:2375-414.
[4]. Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358: 2545-59.
[5]. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008; 358:2560-72.
[6]. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pederson O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348:383-93.
[7]. Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M, Effect of the dual peroxisome proliferator-activated receptor-ag agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomized, dose-ranging study. Lancet 2009; 374 (9684): 126-35.
[8]. Bénardeau A, Benz J, Binggeli A, et al. Aleglitazar, a new potent, and balanced dual PPARa/g agonist for the treatment of type II diabetes. Bioorg Med Chem Lett 2009; 19(9):2468-73.




Reference: PAGE 20 (2011) Abstr 2032 [www.page-meeting.org/?abstract=2032]
Poster: Other topics - Applications
Top