Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark
Pharmacotherapeutic group: Drugs used in diabetes; combinations of oral blood glucose lowering drugs
ATC code: A10BD09
Incresync combines two antihyperglycaemic medicinal products with complementary and distinct mechanisms of action to improve glycaemic control in patients with type 2 diabetes mellitus: alogliptin, a dipeptidyl-peptidase-4 (DPP-4) inhibitor, and pioglitazone, a member of the thiazolidinedione class. Studies in animal models of diabetes showed that concomitant treatment with alogliptin and pioglitazone produced both additive and synergistic improvements in glycaemic control, increased pancreatic insulin content and normalised pancreatic beta-cell distribution.
Alogliptin is a potent and highly selective inhibitor of DPP-4, >10,000-fold more selective for DPP-4 than other related enzymes including DPP-8 and DPP-9. DPP-4 is the principal enzyme involved in the rapid degradation of the incretin hormones, glucagon-like peptide-1 (GLP-1) and GIP (glucosedependent insulinotropic polypeptide), which are released by the intestine and levels are increased in response to a meal. GLP-1 and GIP increases insulin biosynthesis and secretion from pancreatic beta cells, while GLP-1 also inhibits glucagon secretion and hepatic glucose production. Alogliptin therefore improves glycaemic control via a glucose-dependent mechanism, whereby insulin release is enhanced and glucagon levels are suppressed when glucose levels are high.
Pioglitazone effects may be mediated by a reduction of insulin resistance. Pioglitazone appears to act via activation of specific nuclear receptors (peroxisome proliferator activated receptor gamma) leading to increased insulin sensitivity of liver, fat and skeletal muscle cells in animals. Treatment with pioglitazone has been shown to reduce hepatic glucose output and to increase peripheral glucose disposal in the case of insulin resistance.
Fasting and postprandial glycaemic control is improved following treatment with pioglitazone in patients with type 2 diabetes mellitus. The improved glycaemic control is associated with a reduction in both fasting and postprandial plasma insulin concentrations.
HOMA analysis shows that pioglitazone improves beta-cell function as well as increasing insulin sensitivity. Two-year clinical studies have shown maintenance of this effect. In one-year clinical studies, pioglitazone consistently gave a statistically significant reduction in the albumin/creatinine ratio compared to baseline.
The effect of pioglitazone (45 mg monotherapy vs. placebo) was studied in a small 18-week study in type 2 diabetics. Pioglitazone was associated with significant weight gain. Visceral fat was significantly decreased while there was an increase in extra-abdominal fat mass. Similar changes in body fat distribution on pioglitazone have been accompanied by an improvement in insulin sensitivity. In most clinical studies, reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels were observed as compared to placebo with small, but not clinically significant, increases in LDL-cholesterol levels.
In clinical studies of up to two years duration, pioglitazone reduced total plasma triglycerides and free fatty acids, and increased HDL-cholesterol levels compared to placebo, metformin or gliclazide. Pioglitazone did not cause statistically significant increases in LDL-cholesterol levels compared to placebo whilst reductions were observed with metformin and gliclazide. In a 20-week study, as well as reducing fasting triglycerides, pioglitazone reduced postprandial hypertriglyceridaemia through an effect on both absorbed and hepatically synthesised triglycerides. These effects were independent of pioglitazone’s effects on glycaemia and were statistically significantly different to glibenclamide.
Clinical studies conducted to support the efficacy of Incresync involved the co-administration of alogliptin and pioglitazone as separate tablets. However, the results of bioequivalence studies have demonstrated that Incresync film-coated tablets are bioequivalent to the corresponding doses of alogliptin and pioglitazone co-administered as separate tablets.
The co-administration of alogliptin and pioglitazone has been studied as dual therapy in patients initially treated with pioglitazone alone (with or without metformin or a sulphonylurea) and as add-on therapy to metformin.
Administration of 25 mg alogliptin to patients with type 2 diabetes mellitus produced peak inhibition of DPP-4 within 1 to 2 hours and exceeded 93% both after a single 25 mg dose and after 14 days of once-daily dosing. Inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing. When the 4-hour postprandial glucose concentrations were averaged across breakfast, lunch and dinner, 14 days of treatment with 25 mg alogliptin resulted in a mean placebo-corrected reduction from baseline of -35.2 mg/dL.
Both 25 mg alogliptin alone and in combination with 30 mg pioglitazone demonstrated significant decreases in postprandial glucose and postprandial glucagon whilst significantly increasing postprandial active GLP-1 levels at Week 16 compared to placebo (p <0.05). In addition, 25 mg alogliptin alone and in combination with 30 mg pioglitazone produced statistically significant (p <0.001) reductions in total triglycerides at Week 16 as measured by postprandial incremental AUC(0-8) change from baseline compared to placebo.
A total of 3,504 patients with type 2 diabetes mellitus, including 1,908 patients treated with alogliptin and pioglitazone, participated in 4 phase 3 double-blind, placebo- or active-controlled clinical studies conducted to evaluate the effects of co-administered alogliptin and pioglitazone on glycaemic control and their safety. In these studies, 312 alogliptin/pioglitazone-treated patients were ≥ 65 years old. The studies included 1,269 patients with mild renal impairment and 161 patients with moderate renal impairment treated with alogliptin/pioglitazone.
Overall, treatment with the recommended daily dose of 25 mg alogliptin in combination with pioglitazone improved glycaemic control. This was determined by clinically relevant and statistically significant reductions in glycosylated haemoglobin (HbA1c) and fasting plasma glucose compared to control from baseline to study endpoint. Reductions in HbA1c were similar across different subgroups including renal impairment, age, gender and body mass index, while differences between races (e.g. White and non-White) were small. Clinically meaningful reductions in HbA1c compared to control were also observed regardless of baseline background medicinal product dose. Higher baseline HbA1c was associated with a greater reduction in HbA1c. Generally, the effects of alogliptin on body weight and lipids were neutral.
The addition of 25 mg alogliptin once daily to pioglitazone therapy (mean dose = 35.0 mg, with or without metformin or a sulphonylurea) resulted in statistically significant improvements from baseline in HbA1c and fasting plasma glucose at Week 26 when compared to the addition of placebo (Table 2). Clinically meaningful reductions in HbA1c compared to placebo were also observed with 25 mg alogliptin regardless of whether patients were receiving concomitant metformin or sulphonylurea therapy. Significantly more patients receiving 25 mg alogliptin (49.2%) achieved target HbA1c levels of 7.0% compared to those receiving placebo (34.0%) at Week 26 (p = 0.004).
The addition of 25 mg alogliptin once daily to 30 mg pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,867.9 mg) resulted in improvements from baseline in HbA1c at Week 52 that were both non-inferior and statistically superior to those produced by 45 mg pioglitazone in combination with metformin hydrochloride therapy (mean dose = 1,847.6 mg, Table 3). The significant reductions in HbA1c observed with 25 mg alogliptin plus 30 mg pioglitazone and metformin were consistent over the entire 52-week treatment period compared to 45 mg pioglitazone and metformin (p <0.001 at all time points). In addition, mean change from baseline in fasting plasma glucose at Week 52 for 25 mg alogliptin plus 30 mg pioglitazone and metformin was significantly greater than that for 45 mg pioglitazone and metformin (p <0.001). Significantly more patients receiving 25 mg alogliptin plus 30 mg pioglitazone and metformin (33.2%) achieved target HbA1c levels of 7.0% compared to those receiving 45 mg pioglitazone and metformin (21.3%) at Week 52 (p <0.001).
Table 2. Change in HbA1c (%) from baseline with alogliptin 25 mg at Week 26 by placebo-controlled study (FAS, LOCF):
| Study | Mean baseline HbA1c (%) (SD) | Mean change from baseline in HbA1c (%)† (SE) | Placebo-corrected change from baseline in HbA1c ( % )† (2-sided 95% CI) |
|---|---|---|---|
| Add-on combination therapy placebo-controlled studies | |||
| Alogliptin 25 mg once daily with pioglitazone metformin or a sulphonylurea (n = 195) | 8.01 (0.837) | -0.80 (0.056) | -0.61* (-0.80, -0.41) |
FAS = full analysis set
LOCF = last observation carried forward
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values
* p <0.001 compared to placebo or placebo+combination treatment
Table 3. Change in HbA1c (%) from baseline with alogliptin 25 mg by active-controlled study (PPS, LOCF):
| Study | Mean baseline HbA1c (%) (SD) | Mean change from baseline in HbA1c (%)† (SE) | Placebo-corrected change from baseline in HbA1c ( % )† (2-sided 95% CI) |
|---|---|---|---|
| Add-on combination therapy studies | |||
| Alogliptin 25 mg once daily with pioglitazone + metformin vs titrating pioglitazone + metformin | |||
| Change at Week 26 (n = 303) | 8.25 (0.820) | -0.89 (0.042) | -0.47* (-infinity, -0.35) |
| Change at Week 52 (n = 303) | 8.25 (0.820) | -0.70 (0.048) | -0.42* (-infinity, -0.28) |
PPS = per protocol set
LOCF = last observation carried forward
* Non inferiority and superiority statistically demonstrated
† Least squares means adjusted for prior antihyperglycaemic therapy status and baseline values
Incresync is not recommended for patients with severe renal impairment or end-stage renal disease requiring dialysis (see section 4.2).
The efficacy and safety of the recommended doses of alogliptin and pioglitazone in a subgroup of patients with type 2 diabetes mellitus and ≥65 years old were reviewed and found to be consistent with the profile obtained in patients <65 years old.
In a pooled analysis of the data from 13 studies, the overall incidences of cardiovascular death, non fatal myocardial infarction and non-fatal stroke were comparable in patients treated with 25 mg alogliptin, active control or placebo.
In addition, a prospective randomised cardiovascular outcomes safety study was conducted with 5,380 patients with high underlying cardiovascular risk to examine the effect of alogliptin compared with placebo (when added to standard of care) on major adverse cardiovascular events (MACE) including time to the first occurrence of any event in the composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke in patients with a recent (15 to 90 days) acute coronary event. At baseline, patients had a mean age of 61 years, mean duration of diabetes of 9.2 years, and mean HbA1c of 8.0%.
The study demonstrated that alogliptin did not increase the risk of having a MACE compared to placebo [Hazard Ratio: 0.96; 1-sided 99% Confidence Interval: 0-1.16]. In the alogliptin group, 11.3% of patients experienced a MACE compared to 11.8% of patients in the placebo group.
Table 4. MACE Reported in cardiovascular outcomes study:
| Number of Patients (%) | ||
|---|---|---|
| Alogliptin 25 mg | Placebo | |
| N = 2.701 | N = 2.679 | |
| Primary Composite Endpoint [First Event of CV Death, Nonfatal MI and Nonfatal Stroke] | 305 (11,3) | 316 (11,8) |
| Cardiovascular Death* | 89 (3.3) | 111 (4.1) |
| Nonfatal Myocardial Infarction | 187 (6.9) | 173 (6.5) |
| Nonfatal Stroke | 29 (1.1) | 32 (1.2) |
* Overall there were 153 subjects (5.7%) in the alogliptin group and 173 subjects (6.5%) in the placebo group who died (all-cause mortality)
There were 703 patients who experienced an event within the secondary MACE composite endpoint (first event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent revascularization due to unstable angina). In the alogliptin group, 12.7% (344 subjects) experienced an event within the secondary MACE composite endpoint, compared with 13.4% (359 subjects) in the placebo group [Hazard Ratio = 0.95; 1-sided 99% Confidence Interval: 0-1.14].
In controlled clinical studies, the incidence of reports of heart failure with pioglitazone treatment was the same as in placebo, metformin and sulphonylurea treatment groups, but was increased when used in combination therapy with insulin. In an outcome study of patients with pre-existing major macrovascular disease, the incidence of serious heart failure was 1.6% higher with pioglitazone than with placebo when added to therapy that included insulin. However, this did not lead to an increase in mortality in this study. Heart failure has been reported rarely with marketing use of pioglitazone, but more frequently when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure.
In PROactive, a cardiovascular outcome study, 5,238 patients with type 2 diabetes mellitus and pre-existing major macrovascular disease were randomised to pioglitazone or placebo in addition to existing anti-diabetic and cardiovascular therapy, for up to 3.5 years. The study population had an average age of 62 years; the average duration of diabetes was 9.5 years. Approximately one third of patients were receiving insulin in combination with metformin and/or a sulphonylurea. To be eligible, patients had to have had one or more of the following: myocardial infarction, stroke, percutaneous cardiac intervention or coronary artery bypass graft, acute coronary syndrome, coronary artery disease, or peripheral arterial obstructive disease. Almost half of the patients had a previous myocardial infarction and approximately 20% had had a stroke. Approximately half of the study population had at least two of the cardiovascular history entry criteria. Almost all subjects (95%) were receiving cardiovascular medicinal products (beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II antagonists, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates).
Although the study failed regarding its primary endpoint, which was a composite of all-cause mortality, non-fatal myocardial infarction, stroke, acute coronary syndrome, major leg amputation, coronary revascularisation and leg revascularisation, the results suggest that there are no long-term cardiovascular concerns regarding use of pioglitazone. However, the incidences of oedema, weight gain and heart failure were increased. No increase in mortality from heart failure was observed.
In a pooled analysis of the data from 12 studies, the overall incidence of any episode of hypoglycaemia was lower in patients treated with 25 mg alogliptin than in patients treated with 12.5 mg alogliptin, active-control or placebo (3.6%, 4.6%, 12.9% and 6.2%, respectively). The majority of these episodes were mild to moderate in intensity. The overall incidence of episodes of severe hypoglycaemia was comparable in patients treated with 25 mg alogliptin or 12.5 mg alogliptin, and lower than the incidence in patients treated with active-control or placebo (0.1%, 0.1%, 0.4% and 0.4%, respectively). In the prospective randomised controlled cardiovascular outcomes study, investigator reported events of hypoglycemia were similar in patients receiving placebo (6.5%) and patients receiving alogliptin (6.7%) in addition to standard of care.
A clinical study of alogliptin as add-on therapy to pioglitazone demonstrated that there was no clinically relevant increase in hypoglycaemia rate compared to placebo. The incidence of hypoglycaemia was greater when alogliptin was used as triple therapy with pioglitazone and metformin (compared to active-control). This has also been observed with other DPP-4 inhibitors.
Patients (≥ 65 years old) with type 2 diabetes mellitus are considered more susceptible to episodes of hypoglycaemia than patients <65 years old. In a pooled analysis of the data from 12 studies, the overall incidence of any episode of hypoglycaemia was similar in patients ≥65 years old treated with 25 mg alogliptin (3.8%) to that in patients <65 years old (3.6%).
The European Medicines Agency has waived the obligation to submit the results of studies with Incresync in all subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).
The results of bioequivalence studies in healthy subjects demonstrated that Incresync film-coated tablets are bioequivalent to the corresponding doses of alogliptin and pioglitazone co-administered as separate tablets.
Co-administration of 25 mg alogliptin once daily and 45 mg pioglitazone once daily for 12 days in healthy subjects had no clinically relevant effects on the pharmacokinetics of alogliptin, pioglitazone or their active metabolites.
Administration of Incresync with food resulted in no change in overall exposure to alogliptin or pioglitazone. Incresync may, therefore, be administered with or without food.
The following section outlines the pharmacokinetic properties of the individual components of Incresync (alogliptin/pioglitazone) as reported in their respective Summary of Product Characteristics.
The pharmacokinetics of alogliptin has been shown to be similar in healthy subjects and in patients with type 2 diabetes mellitus.
The absolute bioavailability of alogliptin is approximately 100%.
Administration with a high-fat meal resulted in no change in total and peak exposure to alogliptin. Alogliptin may, therefore, be administered with or without food.
After administration of single, oral doses of up to 800 mg in healthy subjects, alogliptin was rapidly absorbed with peak plasma concentrations occurring 1 to 2 hours (median Tmax) after dosing.
No clinically relevant accumulation after multiple dosing was observed in either healthy subjects or in patients with type 2 diabetes mellitus.
Total and peak exposure to alogliptin increased proportionately across single doses of 6.25 mg up to 100 mg alogliptin (covering the therapeutic dose range). The inter-subject coefficient of variation for alogliptin AUC was small (17%).
Following a single intravenous dose of 12.5 mg alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L indicating that the active substance is well distributed into tissues.
Alogliptin is 20-30% bound to plasma proteins.
Alogliptin does not undergo extensive metabolism, 60-70% of the dose is excreted as unchanged active substance in the urine.
Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated alogliptin, 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 a highly selective inhibitor of DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.
In vitro studies indicate that alogliptin does not induce CYP1A2, CYP2B6 and CYP2C9 and does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 at concentrations achieved with the recommended dose of 25 mg alogliptin. Studies in vitro have shown alogliptin to be a mild inducer of CYP3A4, but alogliptin has not been shown to induce CYP3A4 in studies in vivo.
In studies in vitro, alogliptin was not an inhibitor of the following renal transporters; OAT1, OAT3 and OCT2.
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 therapeutic doses.
Alogliptin was eliminated with a mean terminal half-life (T½) of approximately 21 hours.
Following administration of an oral dose of [14C] alogliptin, 76% of total radioactivity was eliminated in the urine and 13% was recovered in the faeces.
The average renal clearance of alogliptin (170 mL/min) was greater than the average estimated glomerular filtration rate (approx. 120 mL/min), suggesting some active renal excretion.
Total exposure (AUC(0-inf)) to alogliptin following administration of a single dose was similar to exposure during one dose interval (AUC(0-24)) after 6 days of once daily dosing. This indicates no time-dependency in the kinetics of alogliptin after multiple dosing.
A single dose of 50 mg alogliptin was administered to 4 groups of patients with varying degrees of renal impairment (CrCl using the Cockcroft-Gault formula): mild (CrCl = >50 to ≤80 mL/min), moderate (CrCl = ≥30 to ≤50 mL/min), severe (CrCl = <30 mL/min) and end-stage renal disease on haemodialysis.
An approximate 1.7-fold increase in AUC for alogliptin was observed in patients with mild renal impairment. However, as the distribution of AUC values for alogliptin in these patients was within the same range as control subjects, no dose adjustment of alogliptin for patients with mild renal impairment is necessary (see section 4.2).
In patients with moderate or severe renal impairment, or end-stage renal disease on haemodialysis, an increase in systemic exposure to alogliptin of approximately 2- and 4-fold was observed, respectively. (Patients with end-stage renal disease underwent haemodialysis immediately after alogliptin dosing. Based on mean dialysate concentrations, approximately 7% of the active substance was removed during a 3-hour haemodialysis session. Therefore, in order to maintain systemic exposures to alogliptin that are similar to those observed in patients with normal renal function, lower doses of alogliptin should be used in patients with moderate or severe renal impairment, or end-stage renal disease requiring dialysis (see above and section 4.2).
Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment compared to control subjects. The magnitude of these reductions was not considered to be clinically relevant. Therefore, no dose adjustment of alogliptin is necessary for patients with mild to moderate hepatic impairment (Child-Pugh scores of 5 to 9). Alogliptin has not been studied in patients with severe hepatic impairment (Child-Pugh score >9).
Age (65-81 years old), gender, race (white, black and Asian) and body weight did not have any clinically relevant effect on the pharmacokinetics of alogliptin. No dose adjustment is necessary (see section 4.2). Paediatric population The pharmacokinetics of alogliptin in children and adolescents <18 years old has not been established. No data are available (see section 4.2).
Following oral administration, pioglitazone is rapidly absorbed and peak serum concentrations of unchanged pioglitazone are usually achieved 2 hours after administration. Proportional increases of the serum concentration were observed for doses from 2-60 mg. Steady-state is achieved after 4-7 days of dosing. Repeated dosing does not result in accumulation of the compound or metabolites. Absorption is not influenced by food intake. Absolute bioavailability is greater than 80%.
The estimated volume of distribution in humans is 19 L.
Pioglitazone and all active metabolites are extensively bound to plasma protein (>99%).
Pioglitazone undergoes extensive hepatic metabolism by hydroxylation of aliphatic methylene groups. This is predominantly via cytochrome P450 2C8 although other isoforms may be involved to a lesser degree. Three of the six identified pioglitazone metabolites are active (M-II, M-III, and M-IV). When activity, concentrations and protein binding are taken into account, pioglitazone and metabolite M-III contribute equally to efficacy. On this basis, M-IV contribution to efficacy is approximately 3-fold that of pioglitazone whilst the relative efficacy of M-II is minimal.
In vitro studies have shown no evidence that pioglitazone inhibits any subtype of cytochrome P450. There is no induction of the main inducible P450 isoenzymes 1A, 2C8/9 and 3A4 in man.
Interaction studies have shown that pioglitazone has no relevant effect on either the pharmacokinetics or pharmacodynamics of digoxin, warfarin, phenprocoumon or metformin. Concomitant administration of pioglitazone with gemfibrozil (an inhibitor of cytochrome P450 2C8) or with rifampicin (an inducer of cytochrome P450 2C8) is reported to increase or decrease, respectively, the serum concentration of pioglitazone (see section 4.5).
Following oral administration of radiolabelled pioglitazone to man, recovered label was mainly in faeces (55%) and a lesser amount in urine (45%). In animals, only a small amount of unchanged pioglitazone can be detected in either urine or faeces. The mean serum elimination half-life of unchanged pioglitazone in man is 5 to 6 hours and for its total active metabolites 16 to 23 hours.
In patients with renal impairment, serum concentrations of pioglitazone and its metabolites are lower than those seen in subjects with normal renal function, but oral clearance of parent substance is similar. Thus, free (unbound) pioglitazone concentration is unchanged (see section 4.2).
Total serum concentration of pioglitazone is unchanged, but with an increased volume of distribution. Intrinsic clearance is, therefore, reduced coupled with a higher unbound fraction of pioglitazone (see section 4.2).
Steady-state pharmacokinetics is similar in patients aged 65 years and over and young subjects (see section 4.2).
The pharmacokinetics of pioglitazone in children and adolescents <18 years old has not been established. No data are available (see section 4.2).
For patients with moderate renal impairment, Incresync 12.5 mg/30 mg should be administered once daily. Incresync is not recommended for patients with severe renal impairment or end-stage renal disease requiring dialysis. No dose adjustment of Incresync for patients with mild renal impairment is necessary (see section 4.2).
Due to its pioglitazone component, Incresync should not be used in patients with hepatic impairment (see section 4.2).
Animal studies of up to 13-weeks duration have been conducted with the combined substances in Incresync.
Concomitant treatment with alogliptin and pioglitazone did not produce new toxicities, nor did it exacerbate any pioglitazone-related findings. No effects on the toxicokinetics of either compound were observed.
Combination treatment with alogliptin and pioglitazone to pregnant rats slightly augmented pioglitazone-related foetal effects of growth retardation and visceral variations, but did not induce embryo-foetal mortality or teratogenicity.
The following data are findings from studies performed with alogliptin or pioglitazone individually.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and toxicology.
The no-observed-adverse-effect level (NOAEL) in the repeated dose toxicity studies in rats and dogs up to 26- and 39-weeks in duration, respectively, produced exposure margins that were approximately 147- and 227-fold, respectively, the exposure in humans at the recommended daily dose of 25 mg alogliptin.
Alogliptin was not genotoxic in a standard battery of in vitro and in vivo genotoxicity studies.
Alogliptin was not carcinogenic in 2-year carcinogenicity studies conducted in rats and mice. Minimal to mild simple transitional cell hyperplasia was seen in the urinary bladder of male rats at the lowest dose used (27 times the human exposure) without establishment of a clear NOEL (no observed effect level).
No adverse effects of alogliptin were observed upon fertility, reproductive performance, or early embryonic development in rats up to a systemic exposure far above the human exposure at the recommended dose. Although fertility was not affected, a slight, statistical increase in the number of abnormal sperm was observed in males at an exposure far above the human exposure at the recommended dose.
Placental transfer of alogliptin occurs in rats.
Alogliptin was not teratogenic in rats or rabbits with a systemic exposure at the NOAELs far above the human exposure at the recommended dose. Higher doses of alogliptin were not teratogenic but resulted in maternal toxicity, and were associated with delayed and/or lack of ossification of bones and decreased foetal body weights.
In a pre- and postnatal development study in rats, exposures far above the human exposure at the recommended dose did not harm the developing embryo or affect offspring growth and development. Higher doses of alogliptin decreased offspring body weight and exerted some developmental effects considered secondary to the low body weight.
Studies in lactating rats indicate that alogliptin is excreted in milk.
No alogliptin-related effects were observed in juvenile rats following repeat-dose administration for 4 and 8 weeks.
In toxicology studies, plasma volume expansion with haemodilution, anaemia and reversible eccentric cardiac hypertrophy was consistently apparent after repeated dosing of mice, rats, dogs and monkeys. In addition, increased fatty deposition and infiltration were observed. These findings were observed across species at plasma concentrations ≤ 4 times the clinical exposure. Foetal growth restriction was apparent in animal studies with pioglitazone. This was attributable to the action of pioglitazone in diminishing the maternal hyperinsulinaemia and increased insulin resistance that occurs during pregnancy thereby reducing the availability of metabolic substrates for foetal growth.
Pioglitazone was devoid of genotoxic potential in a comprehensive battery of in vivo and in vitro genotoxicity assays. An increased incidence of hyperplasia (males and females) and tumours (males) of the urinary bladder epithelium was apparent in rats treated with pioglitazone for up to 2 years.
The formation and presence of urinary calculi with subsequent irritation and hyperplasia was postulated as the mechanistic basis for the observed tumourigenic response in the male rat. A 24-month mechanistic study in male rats demonstrated that administration of pioglitazone resulted in an increased incidence of hyperplastic changes in the bladder. Dietary acidification significantly decreased but did not abolish the incidence of tumours. The presence of microcrystals exacerbated the hyperplastic response but was not considered to be the primary cause of hyperplastic changes. The relevance to humans of the tumourigenic findings in the male rat cannot be excluded.
There was no tumourigenic response in mice of either sex. Hyperplasia of the urinary bladder was not seen in dogs or monkeys treated with pioglitazone for up to 12 months.
In an animal model of familial adenomatous polyposis, treatment with two other thiazolidinediones increased tumour multiplicity in the colon. The relevance of this finding is unknown.
No environmental impact is anticipated from the clinical use of pioglitazone.
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