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Alogliptin: Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
Pioglitazone: Pharmacologic studies indicate that pioglitazone improves insulin sensitivity in muscle and adipose tissue while inhibiting hepatic gluconeogenesis. Unlike sulfonylureas, pioglitazone is not an insulin secretagogue. Pioglitazone is an 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.
Because pioglitazone enhances the effects of circulating insulin (by decreasing insulin resistance), it does not lower blood glucose in animal models that lack endogenous insulin.
Alogliptin and Pioglitazone: In a 26-week, randomized, active-controlled study, patients with type 2 diabetes received alogliptin 25 mg coadministered with pioglitazone 30 mg, alogliptin 12.5 mg coadministered with pioglitazone 30 mg, alogliptin 25 mg alone or pioglitazone 30 mg alone. Patients who were randomized to alogliptin 25 mg with pioglitazone 30 mg achieved a 26. 2% decrease in triglyceride levels from a mean baseline of 214.2 mg/dL compared to an 11.5% decrease for alogliptin alone and a 21.8% decrease for pioglitazone alone. In addition, a 14.4% increase in HDL cholesterol levels from a mean baseline of 43.2 mg/dL was also observed for alogliptin 25 mg with pioglitazone 30 mg compared to a 1.9% increase for alogliptin alone and a 13.2% increase for pioglitazone alone. The changes in measures of LDL cholesterol and total cholesterol were similar between alogliptin 25 mg with pioglitazone 30 mg versus alogliptin alone and pioglitazone alone. A similar pattern of lipid effects was observed in a 26-week, placebo-controlled factorial study.
Alogliptin: Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within 2 to 3 hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were 3- to 4-fold greater with alogliptin (at doses of 25-200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8 hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg alone demonstrated decreases in 2-hour postprandial glucose compared to placebo (-30 mg/dL versus 17.3 mg/dL respectively).
Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within 1 to 2 hours and exceeded 93% across all doses (25 mg, 100 mg, and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.
Pioglitazone: Clinical studies demonstrate that pioglitazone improves insulin sensitivity in insulin-resistant patients. Pioglitazone enhances cellular responsiveness to insulin, increases insulin-dependent glucose disposal, and improves hepatic sensitivity to insulin. In patients with type 2 diabetes, the decreased insulin resistance produced by pioglitazone results in lower plasma glucose concentrations, lower plasma insulin concentrations, and lower A1C values. In controlled clinical trials, pioglitazone had an additive effect on glycemic control when used in combination with a sulfonylurea, metformin, or insulin (see Clinical Studies in the following text). Patients with lipid abnormalities were included in clinical trials with pioglitazone. Overall, patients treated with pioglitazone had mean decreases in serum triglycerides, mean increases in HDL cholesterol, and no consistent mean changes in LDL and total cholesterol. There is no conclusive evidence of macrovascular benefit with pioglitazone or any other antidiabetic medication (see Precautions and Adverse Reactions).
In a 26-week, placebo-controlled, dose-ranging monotherapy study, mean serum triglycerides decreased in the pioglitazone 15 mg, 30 mg, and 45 mg dose groups compared to a mean increase in the placebo group. Mean HDL cholesterol increased to a greater extent in patients treated with pioglitazone than in the placebo-treated patients. There were no consistent differences for LDL and total cholesterol in patients treated with pioglitazone compared to placebo (see Table 1).
Click on icon to see table/diagram/imageIn the two other monotherapy studies (16-weeks and 24-weeks) and in combination therapy studies with sulfonylurea (16 weeks and 24 weeks), metformin 16-weeks and 24-weeks) or insulin (16-weeks and 24-weeks), the lipid results were generally consistent with the data previously mentioned.
Clinical Studies: The coadministration of alogliptin and pioglitazone has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone or on metformin alone. There have been no clinical efficacy studies conducted with OSENI; however, bioequivalence of OSENI with coadministered alogliptin and pioglitazone tablets was demonstrated, and efficacy of the combination of alogliptin and pioglitazone has been demonstrated in four Phase 3 efficacy studies.
In patients with type 2 diabetes, treatment with OSENI produced clinically meaningful and statistically significant improvements in A1C compared to either alogliptin or pioglitazone alone. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with OSENI appears to be related to the degree of A1C elevation at baseline.
Alogliptin and Pioglitazone Co-administration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise: In a 26-week, double-blind, active-controlled study, a total of 655 patients inadequately controlled on diet and exercise alone (mean baseline A1C=8.8%) were randomized to receive alogliptin 25 mg alone, pioglitazone 30 mg alone, alogliptin 12.5 mg with pioglitazone 30 mg, or alogliptin 25 mg with pioglitazone 30 mg once daily. Coadministration of alogliptin 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to either alogliptin 25 mg alone or to pioglitazone 30 mg alone (Table 2). Coadministration of alogliptin 25 mg with pioglitazone 30 mg once daily resulted in statistically significant reductions in fasting plasma glucose (FPG) starting from Week 2 through Week 26 compared to either alogliptin 25 mg or pioglitazone 30 mg alone. A total of 3% of patients receiving alogliptin 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving alogliptin 25 mg alone, and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue.
Improvements in A1C were not affected by gender, age, or baseline BMI.
The mean increase in body weight was similar between pioglitazone alone and alogliptin when coadministered with pioglitazone (see Table 2).
Alogliptin and Pioglitazone Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone: In the second 26-week double-blind, placebo-controlled study, a total of 1554 patients already on metformin (mean baseline A1C=8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of alogliptin alone; 15 mg, 30 mg, or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of alogliptin in combination with 15 mg, 30 mg, or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose=1700 mg) during the treatment period. Coadministration of alogliptin and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to alogliptin alone, or to pioglitazone alone when added to background metformin therapy (see Table 3, Figure 1). A total of 4%, 5%, or 2% of patients receiving alogliptin 25 mg with 15 mg, 30 mg, or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving alogliptin 25 mg, and 10%, 15%, or 9% of patients receiving pioglitazone 15 mg, 30 mg, or 45 mg alone required glycemic rescue.
Improvements in A1C were not affected by gender, age, or baseline BMI.
The mean increase in body weight was similar between pioglitazone alone and alogliptin when coadministered with pioglitazone (see Table 3 and Figure 1).
Alogliptin: Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on Metformin in Combination with Pioglitazone: In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C=8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a 4-week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin (mean dose=1700 mg). Patients who failed to meet pre-specified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy.
In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 to 45 mg at week 26 at Week 52 (Table 4, results shown only for Week 52). A total of 11% of patients who were receiving alogliptin 25 mg in combination with pioglitazone 30 mg and metformin and 22% of patients receiving a dose titration of pioglitazone from 30 mg to 45 mg in combination with metformin required glycemic rescue.
Improvements in A1C were not affected by gender, age, race, or baseline BMI.
The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral (see Table 4).
Alogliptin: Add-on Therapy to a Thiazolidinedione: A 26-week, placebo-controlled study, was conducted to evaluate the efficacy and safety of alogliptin as add-on therapy to pioglitazone in patients with type 2 diabetes. A total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (mean baseline A1C=8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo. Patients were maintained on a stable dose of pioglitazone (mean dose=30 mg) during the treatment period and those who were also previously treated on metformin (median dose=2000 mg) or sulfonylurea (median dose=10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a 4-week single-blind, placebo run-in period prior to randomization. Following randomization, all patients continued to receive instruction on diet and exercise. Patients who failed to meet pre-specified hyperglycemic goals during the 26-week treatment period received glycemic rescue.
The addition of alogliptin 25 mg once daily to pioglitazone therapy resulted in significant improvements from baseline in A1C and FPG at Week 26, when compared to the addition of placebo (see Table 5). A total of 9% of patients who were receiving alogliptin 25 mg and 12% of patients receiving placebo required glycemic rescue.
The improvement in A1C was not affected by gender, age, baseline BMI, or baseline pioglitazone dose. The mean increase in body weight was similar between alogliptin and placebo when given in combination with pioglitazone. Lipid effects were neutral (see Table 5).
Pharmacokinetics: Absorption and Bioavailability: Alogliptin and Pioglitazone: In bioequivalence studies of OSENI 12.5 mg/15 mg and 25 mg/45 mg, the AUC and maximum concentration (Cmax) of both the alogliptin and the pioglitazone component following a single dose of the combination tablet (12.5 mg/15 mg or 25 mg/45 mg) were bioequivalent to alogliptin (12.5 mg or 25 mg) concomitantly administered with pioglitazone (15 mg or 45 mg respectively) tablets under fasted conditions in healthy subjects.
Administration of OSENI 25 mg/45 mg with food resulted in no significant change in overall exposure of alogliptin or pioglitazone. OSENI may therefore be administered with or without food.
Alogliptin: The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal result in no change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food.
Pioglitazone: Following oral administration of pioglitazone hydrochloride, peak concentrations of pioglitazone were observed within 2 hours. Food slightly delays the time to peak serum concentration (Tmax) to 3 to 4 hours, but does not alter the extent of absorption (AUC).
Distribution: Alogliptin: Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.
Alogliptin is 20% bound to plasma proteins.
Pioglitazone: The mean apparent 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 other serum proteins, but with lower affinity. Metabolites M-III and M-IV also are extensively bound (>98%) to serum albumin.
Metabolism: Alogliptin: Alogliptin does not undergo extensive metabolism and 60-71% of the dose is excreted as unchanged drug in the urine.
Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite, and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that the CYP2D6 and CYP3A4, contribute to the limited metabolism of alogliptin.
Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose.
Pioglitazone: Pioglitazone is extensively metabolized by hydroxylation and oxidation; the metabolites also partly convert to glucuronide or sulfate conjugates. Metabolites M-III and M-IV are the major circulating active metabolites in humans. Following once daily administration of pioglitazone, steady-state serum concentrations of both pioglitazone and its major active metabolites, M-III (keto derivative of pioglitazone) and M-IV (hydroxyl derivative of pioglitazone), are achieved within 7 days. At steady-state, M-III and M-IV reach serum concentrations equal to or greater than that of pioglitazone. At steady-state, in both healthy volunteers and patients with type 2 diabetes, pioglitazone comprises approximately 30% to 50% of the peak total pioglitazone serum concentrations (pioglitazone plus active metabolites) and 20% to 25% of the total AUC.
Maximum serum concentration (Cmax), AUC, and trough serum concentrations (Cmin) for pioglitazone and M-III and M-IV, increased proportionally with administered doses of 15 mg and 30 mg per day.
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 gemfibrozil, a strong CYP2C8 inhibitor showed that pioglitazone is a CYP2C8 substrate (see Dosage & Administration and Interactions). Urinary 6β-hydroxycortisol/cortisol ratios measured in patients treated with pioglitazone showed that pioglitazone is not a strong CYP3A4 enzyme inducer.
Excretion and Elimination: Alogliptin: The primary route of elimination of [14C] alogliptin derived radioactivity occurred via renal excretion (76%) with 13% recovered in the feces achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systematic clearance was 14.0 L/hr.
Pioglitazone: 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 its metabolites (M-III and M-IV) range 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.
Special Populations: Renal Impairment: Alogliptin: A single-dose, open-label study was conducted to evaluate the pharmacokinetics of alogliptin 50 mg in patients with chronic renal impairment compared with healthy subjects. In patients with mild renal impairment [creatinine clearance (CrCl) ≥60 to <90 mL/min], an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because increases of this magnitude are not considered clinically relevant, dose adjustment for patients with mild renal impairment is not recommended.
In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate 2-fold increase in plasma AUC of alogliptin was observed. To maintain similar systemic exposures of OSENI to those with normal renal function, the recommended dose of OSENI is 12.5 mg/15 mg, 12.5 mg/30 mg, or 12.5 mg/45 mg once daily in patients with moderate renal impairment.
In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and end-stage renal disease (CrCl <15 mL/min or requiring dialysis), and approximate 3- and 4-fold increase in plasma AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of the drug during a 3-hour dialysis session. OSENI is not recommended for patients with severe renal impairment or ESRD. Coadministration of pioglitazone and alogliptin 6.25 mg once daily based on individual requirements may be considered in these patients.
Pioglitazone: The serum elimination half-life of pioglitazone, M-III and M-IV remains unchanged in patients with moderate (creatinine clearance 30 to 50 mL/min) to severe (creatinine clearance <30 mL/min) renal impairment when compared to subjects with normal renal function. Therefore no dose adjustment in patients with renal impairment is required.
Hepatic Impairment: Alogliptin: Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied. Use caution when administering OSENI to patients with liver disease (see Precautions).
Pioglitazone: Compared with healthy controls, subjects with impaired hepatic function (Child-Pugh Grade B/C) have an approximate 45% reduction in pioglitazone and total pioglitazone (pioglitazone, M-III and M-IV) mean peak concentrations but no change in the mean AUC values. Therefore, no dose adjustment in patients with hepatic impairment is required.
There are postmarketing reports of liver failure with pioglitazone and clinical trials have generally excluded patients with serum ALT >2.5 times the upper limit of the reference range. Use caution in patients with liver disease (Precautions).
Gender: Alogliptin: No dose adjustment is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Pioglitazone: The mean Cmax and AUC values of pioglitazone were increased 20% to 60% in women compared to men. In controlled clinical trials, A1C decreases from baseline were generally greater for females than for males (average mean difference in A1C 0.5%). Because therapy should be individualized for each patient to achieve glycemic control, no dose adjustment is recommended based on gender alone.
Geriatric: Alogliptin: No dose adjustment is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Pioglitazone: In healthy elderly subjects, peak serum concentrations of pioglitazone and total pioglitazone are not significantly different, but AUC values are approximately 21% higher than those achieved in younger subjects. The mean terminal half-life values of pioglitazone were also longer in elderly subjects (about 10 hours) as compared to younger subjects (about 7 hours). These changes were not of a magnitude that would be considered clinically relevant.
Pediatrics: Alogliptin: Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.
Pioglitazone: Safety and efficacy of pioglitazone in pediatric patients have not been established. Pioglitazone is not recommended for use in pediatric patients (see Use in Children under Precautions).
Race and Ethnicity: Alogliptin: No dose adjustment is necessary based on race. Race (White, Black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.
Pioglitazone: Pharmacokinetic data among various ethnic groups are not available.
Drug-Drug Interactions: Coadministration of alogliptin 25 mg once daily with a CYP2C8 substrate, pioglitazone 45 mg once daily for 12 days had no clinically meaningful effects on the pharmacokinetics of pioglitazone and its active metabolites. Specific pharmacokinetic drug interaction studies with OSENI have not been performed, although such studies have been conducted with the individual components of OSENI (alogliptin and pioglitazone).
Alogliptin: In Vitro Assessment of Drug Interactions: In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.
In Vivo Assessment of Drug Interactions: Effects of Alogliptin on Other Drugs: In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (see Figure 2). No dose adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies (see Figure 2).
Effects of Other Drugs on the Pharmacokinetics of Alogliptin: There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described in Figure 3 and Tables 6 and 7 (see Figure 3, Tables 6 and 7).
Non-Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Alogliptin and Pioglitazone: No carcinogenicity, mutagenicity, or impairment of fertility studies have been conducted with OSENI. The following data are based on findings in studies performed with alogliptin or pioglitazone individually.
Alogliptin: Rats were administered oral doses of 75, 400, and 800 mg/kg alogliptin for 2 years. No drug-related tumors were observed up to 75 mg/kg or approximately 32 times the maximum recommended clinical dose of 25 mg, based on AUC exposure. At higher doses (approximately 308 times the maximum recommended clinical dose of 25 mg), a combination of thyroid C-cell adenomas and carcinomas increased in male but not female rats. No drug-related tumors were observed in mice after administration of 50, 150, or 300 mg/kg alogliptin for 2 years, or up to approximately 51-times the maximum recommended clinical dose of 25 mg, based on AUC exposure.
Alogliptin was not mutagenic or clastogenic, with and without metabolic activation, in the Ames test with S. typhimurium and E. coli or the cytogenetic assay in mouse lymphoma cells. Alogliptin was negative in the in vivo mouse micronucleus study.
In a fertility study in rats, alogliptin had no adverse effects on early embryonic development, mating, or fertility, at doses up to 500 mg/kg, or approximately 172-times the clinical dose based on plasma drug exposure (AUC).
Pioglitazone: A two year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the MRHD of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg and above (approximately equal to the MRHD based on mg/m2). A two year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg (approximately 11 times the MRHD based on mg/m2). No drug-induced tumors were observed in any organ.
Pioglitazone was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay.
No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone daily prior to and throughout mating and gestation (approximately 9 times the MRHD based on mg/m2).
Animal Toxicology and/or Pharmacology: Pioglitazone: Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone (approximately 11, 1, and 2 times the MRHD for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg (approximately 35 times the MRHD based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the MRHD based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the MRHD based on mg/m2).
