Pharmacology: Mechanism of Action:
Actosmet combines 2 antihyperglycemic agents with complementary mechanisms of action to improve glycemic control in patients with the type 2 diabetes: Pioglitazone hydrochloride, a member of the thiazolidinedione class, and metformin hydrochloride, a member of the biguanide class. Thiazolidinediones are insulin-sensitizing agents that act primarily by enhancing peripheral glucose utilization, whereas biguanides act primarily by decreasing endogenous hepatic glucose production.
Pioglitazone depends on the presence of insulin for its metabolism of action. Piolitazone decreases insulin resistance in the periphery and in the liver resulting in increased insulin-dependent glucose disposal, and decreased hepatic glucose output. Unlike sulfonylureas, piogltiazone is not an insulin secretagogue. Pioglitazone is a potent and highly selective agonist for peroxisome proliferator-activated receptor-γ (PPARγ). PPAR receptors are found in tissues important for insulin action eg, 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 eg, 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 endogeous insulin.
Metformin hydrochloride improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreased hepatic glucose production, decreased intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see General: Metformin Hydrochloride under Precautions) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacodynamics: Clinical Effects: Pioglitazone Hydrochloride:
Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, improves hepatic sensitivity to insulin, and improves dysfunctional glucose homeostasis. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin levels, and lower HbA1c values. Based on results from an open-label extension study, the glucose-lowering effects of pioglitazone appear to persist for at least 1 year. In controlled clinical studies, pioglitazone in combination with metformin had an additive effect on glycemic control.
Patients with lipid abnormalities were included in placebo-controlled monotherapy clinical studies with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in triglycerides, mean increases in HDL-cholesterol, and no consistent mean changes in LDL-cholesterol and total cholesterol compared to the placebo group. A similar pattern of results was seen in 16- and 24-week combination therapy studies of pioglitazone with metformin.
Pharmacokinetics: Absorption and Bioavailability:
In bioequivalence studies of Actosmet 15 mg/850 mg, the area under the curve (AUC) and maximum concentration (Cmax
) of both the pioglitazone and the metformin component following a single dose of the combination tablet were bioequivalent to Actos 15 mg concomitantly administered with metformin hydrochloride 850-mg tablet under fasted conditions in healthy subjects (see Table 1).
Click on icon to see table/diagram/image
Administration of Actosmet 15 mg/850 mg with food resulted in no change in overall exposure of pioglitazone. With metformin there was no change in AUC, however mean peak serum concentration of metformin was decreased by 28% when administered with food. A delayed time to peak serum concentration was observed for both components (1.9 hrs for pioglitazone and 0.8 hrs for metformin) under fed conditions. These changes are not likely to be clinically significant.
Following oral administration, in the fasting state, pioglitazone is 1st measurable in serum within 30 min, with peak concentrations observed within 2 hrs. Food slightly delays the time to peak serum concentration to 3-4 hrs, but does not alter the extent of absorption.
The absolute bioavailabifity of a metformin 500-mg tablet given under fasting conditions is approximately 50 or 60%. Studies using single oral doses of metformin tablets of 500 mg to 1500 mg and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.
Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration, a 25% lower AUC in plasma concentration versus time curve and a 35 min prolongation of time to peak plasma concentration following administration of a single 850-mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution: Pioglitazone Hydrochloride:
The mean apparent volume of distribution (V/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 other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
The apparent volume of distribution (V/F) of metformin following single oral doses of 850 mg averaged 654±358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady-state plasma concentrations of metformin are reached within 24-48 hrs and are generally <1 mcg/mL. During controlled clinical trials, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
Metabolism, Elimination and Excretion: Pioglitazone Hydrochloride:
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 30-50% of the total peak serum concentrations and 20-25% of the total AUC.
data demonstrate that multiple CYP isoforms are involved in the metabolism of pioglitazone. The cytochrome P4-50 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 (see Precautions and Interactions: Pioglitazone Hydrochloride). Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Following oral administration, approximately 15-30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible and the drug is excreted primarily as metabolites and the 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 3-7 hrs and 16-24 hrs, respectively. Pioglitazone has an apparent clearance, CL/F, calculated to be 5-7 L/hr.
IV single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance (CrCl) which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hrs, with a plasma elimination half-life of approximately 6.2 hrs. In blood, the elimination half-life is approximately 17.6 hrs, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations: Renal Insufficiency: Pioglitazone Hydrochloride:
The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (CrCl 30-60 mL/min) to severe (CrCl <30 mL/min) renal impairment when compared to normal subjects.
In patients with decreased renal function (based on CrCl), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in CrCl (see Clinical Effects and Pharmacokinetics: Metformin Hydrochloride under Actions, Contraindications and Warnings). Since metformin is contraindicated in patients with renal impairment, Actosmet is also contraindicated in these patients.
Hepatic Insufficiency: Pioglitazone Hydrochloride:
Compared with normal controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone mean peak concentrations but no change in the mean AUC values.
Therapy with Actosmet should not be initiated if the patient exhibits clinical evidence of active liver disease or serum transaminase levels (ALT) exceed 2.5 times the upper limit of normal (see General: Pioglitazone Hydrochloride under Precautions).
No pharmacokinetic studies of metformin have been conducted in subjects with hepatic insufficiency.
Elderly: Pioglitazone Hydrochloride:
In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are slightly higher and the terminal half-life values slightly longer than for younger subjects. These changes were not of a magnitude that would be considered clinically relevant.
Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cmax
is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.
Actosmet treatment should not be initiated in patients ≥80 years unless measurement of creatinine clearance demonstrates that renal function is not reduced (see Dosage & Administration and Warnings).
Pediatrics: Pioglitazone Hydrochloride:
Pharmacokinetic data in the pediatric population are not available. Use in pediatric patients is not recommended for the treatment of diabetes due to lack of long-term safety data. Risks including fractures and other adverse effects associated with pioglitazone, one of the components of Actosmet, have not been determined in this population (see Warnings and Precautions).
After administration of a single oral metformin 500-mg tablet with food, geometric mean metformin Cmax
and AUC differed <5% between pediatric type 2 diabetic patients (12-16 years) and gender- and weight-matched healthy adults (20-45 years), and all with normal renal function.
Gender: Pioglitazone Hydrochloride:
As monotherapy and in combination with sulfonylurea, metformin, or insulin, pioglitazone improved glycemic control in both males and females. The mean C max
and AUC values were increased 20-60% in females. In controlled clinical trials, decreases from baseline in HbA1c were generally greater for females than for males (average mean difference in HbA1c 0.5%). Since therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males=19, females=16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.
Ethnicity: Pioglitazone Hydrochloride:
Pharmacokinetic data among various ethnic groups are not available.
No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51) and Hispanics (n=24).
Co-administration of a single dose of metformin (1000 mg) and pioglitazone after 7 days of pioglitazone (45 mg) did not alter the pharmacokinetics of the single dose of metformin. Specific pharmacokinetic drug interaction studies with Actosmet have not been performed, although such studies have been conducted with the individual pioglitazone and metformin components.
The following drugs were studied in healthy volunteers with co-administration of pioglitazone 45 mg once daily. Results are listed as follows: Oral Contraceptives:
Co-administration of pioglitazone (45 mg once daily) and an oral contraceptive (norethindrone 1 mg plus ethinyl estradiol 0.035 mg once daily) for 21 days, resulted in 11% and 11-14% decrease in ethinyl estradiol AUC(0-24 hr)
respectively. There were no significant changes in norethindrone AUC(024 hr)
. In view of the high variability of ethinyl estradiol pharmacokinetics, the clinical significance of this finding is unknown.
Administration of pioglitazone for 15 days followed by a single 7.5 mg dose of midazolam syrup resulted in a 26% reduction in midazolam Cmax
Co-administration of pioglitazone for 7 days with nifedipine ER 30 mg administered orally once daily for 4 days to male and female volunteers resulted in a ratio of least square mean (90% CI) values for unchanged nifedipine of 0.83 (0.73-0.95) for Cmax
and 0.88 (0.8-0.96) for AUC. In view of the high variability of nifedipine pharmacokinetics, the clinical significance of this finding is unknown.
Co-administration of pioglitazone for 7 days with ketoconazole 200 mg administered twice daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 1.14 (1.06-1.23) for Cmax
, 1.34 (1.26-1.41) for AUC and 1.87 (1.71-2.04) for Cmin
Co-administration of pioglilazone for 7 days with atorvastatin calcium (Lipitor) 80 mg once daily resulted in a ratio of least square mean (90% CI) values for unchanged pioglitazone of 0.69 (0.57-0.85) for Cmax
, 0.76 (0.65-0.88) for AUC and 0.96 (0.87- 1.05) for Cmin
. For unchanged atorvastatin the ratio of least square mean (90% CI) values were 0.77 (0.66-0.9) for Cmax
, 0.86 (0.78-0.94) for AUC and 0.92 (0.82-1.02) for Cmin
See Precautions and Interactions: Pioglitazone Hydrochloride.
Concomitant administration of gemfibrozil (oral 600 mg twice daily), an inhibitor of CYP2C8, with pioglitazone (oral 30 mg) in 10 healthy volunteers pre-treated for 2 days prior with gemfibrozil (oral 600 mg twice daily) resulted in pioglitazone exposure (AUC0-24 hr
) being 226% of the pioglitazone exposure in the absence of gemfibrozif (see Precautions and Interactions: Pioglitazone Hydrochloride).
Concomitant administration of rifampin (oral 600 mg once daily), an inducer of CYP2CB with pioglitazone (oral 30 mg) in 10 healthy volunteers pretreated for 5 days prior with rifampin (oral 600 mg once daily) resulted in a decrease in the AUC of pioglitazone by 54% (see Precautions and Interactions: Poglitazone Hydrochloride).
In other drug-drug interaction studies, pioglitazone had no significant effect on the pharmacokinetics of fexofenadine, glipizide, digoxin, warfarin, ranitidine hydrochloride or theophylline.
See Precautions and Interactions: Metformin Hydrochloride.
Toxicology: Animal Toxicity: Pioglitazone Hydrochloride:
Heart enlargement has been observed in mice (100 mg/kg), rats (≥4 mg/kg) and dogs (3 mg/kg) treated orally with the pioglitazone hydrochloride component of Actosmet (approximately 11, 1 and 2 times the maximum recommended human oral dose for mice, rats and dogs, respectively, based on mg/m2
). In a 1-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg daily (approximately 35 times the maximum recommended human oral dose based on mg/m2
). Heart enlargement was seen in a 13-week study in monkeys at oral doses of ≥8.9 mg/kg (approximately 4 times the maximum recommended human oral dose based on mg/m2
), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2