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Ragaglitazar: The Pharmacokinetics, Pharmacodynamics, and Tolerability of a Novel Dual PPAR and Agonist in Healthy Subjects and Patients with Type 2 Diabetes

From Global Development (B. K. Skrumsager, P. G. Drake, B. Edsberg) and Pharmacokinetics (K. K. Nielsen), Novo Nordisk A/S, Bagsværd, Denmark, and AAI Deutschland GmbH & Co KG, Neu-Ulm, Germany (M. Müller, G. Pabst).

Ragaglitazar is a novel dual peroxisome proliferator-activated receptor (PPAR) and agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. These studies assessed single-dose pharmacokinetics and tolerability of ragaglitazar in healthy subjects, as well as multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of ragaglitazar in healthy subjects and in patients with type 2 diabetes. Healthy subjects received a single oral dose (1-120 mg), and healthy subjects and type 2 diabetic patients received a loading dose and thereafter once-daily doses (0.5-16 mg) of ragaglitazar for 6 and 20 days, respectively. Ragaglitazar was rapidly absorbed (t_max: 1.5-1.7 h), with mean AUC_{0-24 h} and C_max proportional to dose after single and multiple dosing; t_1/2 was 80 hours following a single dose and 104 hours in healthy subjects and 122 hours in patients after multiple dosing. Administration of 4 mg ragaglitazar to patients (n = 4) for 21 days resulted in mean decreases from baseline in fasting levels of plasma glucose (18%), C-peptide (18%), fructosamine (6%), triglycerides (36%), free fatty acids (49%), total cholesterol (11%), low-density lipoprotein (LDL) cholesterol (21%), and very low-density lipoprotein (VLDL) cholesterol (15%), as well as an increase in high-density lipoprotein (HDL) cholesterol (33%). Overall, ragaglitazar was well tolerated; with multiple dosing, there was a higher incidence of adverse events for patients that, at the highest dose level (16 mg), included peripheral edema and anemia.

Key Words: Ragaglitazar • type 2 diabetes • diabetic dyslipidemia • pharmacokinetics • pharmacodynamics • tolerability

Address for reprints: Birte K. Skrumsager, Novo Nordisk A/S, Building 9E1.18, Krogshøjvej, Bagsværd, Denmark, DK-2880.

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