PubChem compound: 145994868
Albiglutide is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion. Albiglutide also slows gastric emptying.
Albiglutide lowers fasting glucose and reduces postprandial glucose excursions. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide.
In patients with type 2 diabetes who received 2 doses of albiglutide 32 mg (Day 1 and 8), a statistically significant reduction (24%) in postprandial glucose AUC(0.5-4.5h) was observed compared to placebo following a standardised breakfast meal on Day 9.
A single dose of albiglutide 50 mg did not impair the glucagon, epinephrine, norepinephrine, cortisol or growth hormone counter-regulatory hormone response to hypoglycaemia.
Albiglutide slowed gastric emptying compared with placebo for both solids and liquids when 100 mg was administered as a single dose in healthy subjects. For solids, gastric emptying t1/2 increased from 1.14 h to 2.23 h (p=0.0112). For liquids, gastric emptying t1/2 increased from 0.28 h to 0.69 h (p=0.0018).
Following SC administration of a single 30 mg dose to subjects with type 2 diabetes, maximum concentrations were reached 3 to 5 days post dose with mean peak albiglutide concentration (Cmax) of 1.74 mcg/ml and mean area under the time-concentration curve (AUC) of 465 mcg.h/ml. The average weekly steady state concentrations following SC administration of 30 mg or 50 mg albiglutide estimated in the population PK analyses from phase III patient studies were approximately 2.6 mcg/ml and 4.4 mcg/ml, respectively. Steady-state exposures are achieved following 3-5 weeks of once-weekly administration. Exposures at the 30 mg and 50 mg dose levels were consistent with a dose-proportional increase. However, in healthy volunteers following 50 mg the steady state concentration was 7.39 µg/ml at day 36, thus higher than population PK analyses from phase III patient studies predicted. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm.
The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 litres. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed.
Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes.
The mean apparent clearance of albiglutide is 67 ml/h with an elimination half-life of approximately 5 days based on estimations from the population PK analyses from phase III patient studies and measured values.
In a population pharmacokinetic analysis including a phase III trial in patients with mild, moderate and severe renal impairment, exposures were increased by approximately 30 to 40% in severe renal impairment compared to those observed in type 2 diabetic patients with normal renal function. In addition, a clinical pharmacology study showed a similar increased exposure for patients with moderate or severe renal impairment or those on haemodialysis relative to patients without renal impairment. These differences were not considered clinically relevant.
No clinical studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of albiglutide. Therapeutic proteins such as albiglutide are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of albiglutide.
Based on the results of population pharmacokinetic analyses, there is no clinically relevant effect of gender on clearance.
Based on the results of population pharmacokinetic analyses that included Caucasian, African American/African, Asian and Hispanic/Non-Hispanic patients, race and ethnicity had no clinically meaningful effect on the pharmacokinetics of albiglutide clearance.
Japanese patients showed approximately 30 to 40% higher exposures than Caucasians, likely attributable to lower body weight. This effect was not considered clinically relevant.
Age had no clinically relevant effect on the pharmacokinetics of albiglutide based on a population pharmacokinetic analysis of subjects aged 24-83 years.
Body weight has no clinically relevant effect on albiglutide AUC over the range 44 to 158 kg. A 20% increase in body weight resulted in an approximate 18.5% increase in clearance.
No pharmacokinetic data are available in paediatric patients.
Non-clinical data reveal no special hazards for humans based on studies of safety pharmacology or repeatdose toxicity. As albiglutide is a recombinant protein, no genotoxicity studies have been conducted.
In a 52-week monkey study, there was a small increase in pancreas tissue weight at 50 mg/kg/week (75 times clinical exposure based on AUC) associated with acinar cell hypertrophy. A small increase in islet cell number was also observed. The pancreas changes were not associated with histomorphologic abnormalities or evidence of increased proliferation.
No carcinogenicity studies have been performed with albiglutide due to immunogenicity in rodents. Thyroid C-cell tumours were observed in 2 year rodent carcinogenicity studies with other GLP-1 receptor agonists. Increased serum calcitonin levels have been associated with the thyroid C-cell hyperplasia and tumours observed in rodent studies with these other agents. Albiglutide also produced dose-dependent increases in serum calcitonin levels in a 21-day study in mice, suggesting that thyroid tumours in rodents are a theoretical possibility for albiglutide as well. There were no albiglutide related findings in thyroids of monkeys given up to 50 mg/kg/week for up to 52 weeks (75 times clinical exposure based on AUC). The clinical relevance of the observed thyroid C-cell tumours in rodents is unknown.
In reproductive toxicology studies with albiglutide in mice, there were no effects on mating or fertility at doses up to 50 mg/kg/day (at low multiple of clinical exposure). Reductions in oestrous cycles were observed at 50 mg/kg/day, a dose associated with maternal toxicity (body weight loss and reduced food consumption). Effects on embryo-foetal development (embryo-foetal lethality and skeletal variations) were observed at 50 mg/kg/day (at low multiple of clinical exposure). Offspring of mice dosed with 50 mg/kg/day during organogenesis had reduced weight during the pre-weaning period (which recovered after weaning), dehydration and coldness, and a delay in balanopreputial separation. No effects were seen at 5 mg/kg/day (at exposures similar to clinical exposure).
In pre- and postnatal development studies in mice administered albiglutide during pregnancy or while nursing, reduced pre-weaning body weight of F1 offspring was observed at ≥1 mg/kg/day (at exposures below clinical exposure). Reduced F1 body weight reversed post-weaning with the exception of F1 females from dams treated perinatally (end of gestation to 10 days postpartum) at ≥5 mg/kg/day with no other effects on development. Trace levels of albiglutide were detected in plasma of offspring. It is unknown whether the reduced offspring body weight was caused by a direct albiglutide effect on the offspring or secondary to effects on the dam.
Increased mortality and morbidity were seen at all doses (≥1 mg/kg/day) in lactating females in mouse preand postnatal development studies. Mortalities have not been observed in previous toxicology studies in nonlactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is much lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are considered not relevant to humans.
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