Pharmacology: Pharmacodynamics: Mechanism of Action: Asenza Plus combines two antihyperglycemic agents with different mechanisms of action to improve glycemic control in patients with type 2 diabetes: Pioglitazone hydrochloride, a member of the thiazolidinedione class, and Glimepiride, a member of the sulfonylurea class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas sulfonylureas are insulin secretogogues that act primarily by stimulating release of insulin from functioning pancreatic beta cells.
Pioglitazone HCl: Pioglitazone depends on the presence of insulin for its mechanism of action. Pioglitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-gamma (PPARγ). PPAR receptors are found in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPARγ nuclear receptors modulates the transcription of a number of insulin responsive genes involved in the control of glucose and lipid metabolism.
In animal models of diabetes, Pioglitazone reduces the hyperglycemia, hyperinsulinemia, and hypertriglyceridemia characteristic of insulin-resistant states such as type 2 diabetes. The metabolic changes produced by Pioglitazone result in increased responsiveness of insulin dependent tissues and are observed in numerous animal models of insulin resistance.
Since Pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Glimepiride: The primary mechanism of action of Glimepiride in lowering blood glucose appears to be dependent on stimulating the release of insulin from functioning pancreatic beta cells. In addition, extrapancreatic effects may also play a role in the activity of sulfonylureas such as Glimepiride. This is supported by both preclinical and clinical studies demonstrating that Glimepiride administration can lead to increased sensitivity of peripheral tissues to insulin. These findings are consistent with the results of a long-term, randomized, placebo-controlled trial in which Glimepiride therapy improved postprandial insulin/C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin/C-peptide levels. However, as with other sulfonylureas, the mechanism by which Glimepiride lowers blood glucose during long-term administration has not been clearly established.
Pharmacokinetics: Pioglitazone HCl is rapidly absorbed after oral administration. Peak plasma concentrations are obtained within 2 hours and bioavailability exceeds 80%. Pioglitazone is more than 99% bound to plasma proteins. It is extensively metabolized by cytochrome P450 isoenzymes CYP3A4 and CYP2C9 to both active and inactive metabolites. It is excreted in the urine and feces and has a plasma half-life of up to 7 hours. The active metabolites have a half-life of up to 24 hours.
Absorption: Pioglitazone HCl: Following oral administration, in the fasting state, Pioglitazone is first measurable in serum within 30 minutes, with peak concentrations observed within 2 hours. Food slightly delays the time to peak serum concentration to 3 to 4 hours, but does not alter the extent of absorption.
Glimepiride: After oral administration, Glimepiride is completely (100%) absorbed from the GI tract. Studies with single oral doses in normal subjects and with multiple oral doses in patients with type 2 diabetes have shown significant absorption of Glimepiride within 1 hour after administration and Cmax at 2 to 3 hours. When Glimepiride was given with meals, the mean Tmax was slightly increased (12%) and the mean Cmax and the total area under the serum concentration-time curve (AUC) were slightly decreased (8% and 9%, respectively).
Distribution: Pioglitazone HCl: The mean apparent volume of distribution (Vd/F) of Pioglitazone following single-dose administration is 0.63±0.41 (mean ± SD) L/kg of body weight. Pioglitazone is extensively protein bound (>99%) in human serum, principally to serum albumin. Pioglitazone also binds to their serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
Glimepiride: After intravenous (IV) dosing in normal subjects, Vd/F was 8.8 L (113 mL/kg), and the total body clearance (CL) was 47.8 mL/min. Protein binding was greater than 99.5%.
Metabolism: Pioglitazone HCl: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-II and M-IV (hydroxy derivatives of Pioglitazone) and M-III (keto derivative of Pioglitazone) are pharmacologically active in animal models of type 2 diabetes. In addition to Pioglitazone, M-III and M-IV are the principal drug-related species found in human serum following multiple dosing. At steady-state, in both healthy volunteers and in patients with type 2 diabetes, Pioglitazone comprises approximately 30% to 50% of the total [peak serum concentrations and 20% to 25% of the total AUC].
In vitro data demonstrate that multiple CYP isoforms are involved in the metabolism of Pioglitazone. The cytochrome P450 isoforms involved are CYP2C8 and, to a lesser degree, CYP3A4 with additional contributions from a variety of other isoforms including the mainly extrahepatic CYP1A1. In vivo studies of Pioglitazone in combination with P450 inhibitors and substrates have been performed. Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with Pioglitazone showed that Pioglitazone is not a strong CYP3A4 enzyme inducer.
Glimepiride: Glimepiride is completely metabolized by oxidative biotransformation after either an IV or oral dose. The major metabolites are the cyclohexyl hydroxy methyl derivative (M1) and the carboxyl derivative (M2). CYP2C9 has been shown to be involved in the biotransformation of Glimepiride to M1. M1 is further metabolized to M2 by one or several cytosolic enzymes. M1, but not M2, possesses about 1/3 of the pharmacological activity as compared to its parent in an animal model; however, whether the glucose-lowering effect of M1 is clinically meaningful is not clear.
Excretion and Elimination: Pioglitazone HCl: Following oral administration, approximately 15% to 30% of the Pioglitazone dose is recovered in the urine. Renal elimination of Pioglitazone is negligible and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.
The mean serum half-life of Pioglitazone and total Pioglitazone ranges from 3 to 7 hours and 16 to 24 hours, respectively. Pioglitazone has an apparent clearance, CL/f, calculated to be 5 to 7 L/hr.
Glimepiride: When C-glimepiride was given orally, approximately 60% of the total radioactivity was recovered in the urine in 7 days and M1 (predominant) and M2 accounted for 80-90% of that recovered in the urine. Approximately 40% of the total radioactivity was recovered in feces and M1 and M2 (predominant) accounted for about 70% of that recovered in feces. No parent drug was recovered from urine or feces. After IV dosing in patients, no significant biliary excretion of Glimepiride or its M1 metabolite has been observed.