Combination of 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.
The results of bioequivalence studies in healthy subjects demonstrated that alogliptin/pioglitazone fixed-dose combination 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 alogliptin/pioglitazone with food resulted in no change in overall exposure to alogliptin or pioglitazone. Alogliptin/pioglitazone may, therefore, be administered with or without food.
The following section outlines the pharmacokinetic properties of the individual components of alogliptin/pioglitazone fixed-dose combination 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.
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.
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. Paediatric population The pharmacokinetics of alogliptin in children and adolescents <18 years old has not been established. No data are available.
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.
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.
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.
Steady-state pharmacokinetics is similar in patients aged 65 years and over and young subjects.
The pharmacokinetics of pioglitazone in children and adolescents <18 years old has not been established. No data are available.
For patients with moderate renal impairment, alogliptin/pioglitazone 12.5 mg/30 mg should be administered once daily. Alogliptin/pioglitazone combination is not recommended for patients with severe renal impairment or end-stage renal disease requiring dialysis. No dose adjustment of alogliptin/pioglitazone for patients with mild renal impairment is necessary.
Due to its pioglitazone component, alogliptin/pioglitazone should not be used in patients with hepatic impairment.
Animal studies of up to 13-weeks duration have been conducted with the combined substances in alogliptin/pioglitazone.
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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