Equipotency of insulin glargine 300 and 100 U/mL with intravenous dosing but differential bioavailability with subcutaneous dosing in dogs

Abstract

Aims Insulin glargine 300 U/mL (Gla‐300) contains the same units versus glargine 100 U/mL (Gla‐100) in three‐fold lower volume, and higher subcutaneous (SC) doses are required in people with diabetes. To investigate blood glucose (BG) lowering potency, Gla‐300 and Gla‐100 were compared after intravenous (IV, for 4 h) and SC (for 24 h) injection in healthy Beagle dogs. Materials and methods The dose of 0.15 U/kg Gla‐300 and Gla‐100 was injected IV in 12 dogs. BG, C‐peptide, glucagon and the active metabolite 21A‐Gly‐human insulin (M1; liquid chromatography‐tandem mass spectrometry method) were measured. Twelve other dogs were studied after SC injection of 0.3 U/kg Gla‐300 and Gla‐100. Results After IV injection, Gla‐300 and Gla‐100 were equally potent [BG_AUC0‐4 h ratio 1.01 (95% confidence interval, 0.94; 1.09)]. After SC injection, BG decreased slower and less with Gla‐300. Similar metabolism of Gla‐300 and Gla‐100 to M1 occurred with IV dosing [M1_AUC0‐1 h ratio 0.99 (95% confidence interval, 0.82; 1.22)], but with SC dosing M1_Cmax and AUC0‐24h were 44% and 17% lower; mean residency time and bioavailability were 32% longer and 50% lower, with Gla‐300. Conclusions IV Gla‐300 and Gla‐100 have the equivalent of BG‐lowering potency and M1 metabolism. SC Gla‐300 has lower M1 bioavailability with a reduced BG‐lowering effect and need for greater doses versus Gla‐100.

Insulins for the long term management of diabetes mellitus in dogs: a review

“…However, this may have reflected methodological differences between the studies. In a separate study which directly compared the 300 and 100 U/mL formulations in healthy dogs, the former was associated with a slower and less marked decrease in glucose concentration, and mean residency time of the analogue insulin was 32% longer, and bioavailability was 50% lower compared to the latter formulation [ 41 ]. This suggests that the higher concentration formulation may have a more protracted duration of action, and may be a better choice for once daily insulin therapy.…”

Day‐to‐day variability of porcine lente, insulin glargine 300 U/mL and insulin degludec in diabetic dogs

“…When administered to the SC, IGla300 shows reduced blood glucose lowering effects compared to insulin glargine 100 U/mL and other insulin formulations, both in clinical trials and in euglycemic‐clamp studies in people and in dogs 11,27 . It was recently demonstrated in dogs that this is caused by longer residence time of the insulin in the SC, allowing it more time to be exposed to local degrading enzymes and resulting in lower bioavailability 27 . As such, clinical use of IGla300 in dogs would require higher doses compared to other formulations.…”

Insulin Centennial: Milestones influencing the development of insulin preparations since 1922

“…Glargine U300 shows equivalent glycaemic control to glargine U100 in people with T2DM, although a slightly higher dose ($15%) is required possibly due to local enzymatic degradation at the site of injection. 126 Also, a lower risk of hypoglycaemia (day and night), especially during the initial titration period is observed with glargine U300. 127 In people with T1DM, when administered at equipotent doses glargine 300 shows a smoother and more prolonged absorption than glargine U100.…”

“…Its metabolism is identical to U100, reaffirming that M1 (Gly A21 ‐human insulin) is the active component. Glargine U300 shows equivalent glycaemic control to glargine U100 in people with T2DM, although a slightly higher dose (~15%) is required possibly due to local enzymatic degradation at the site of injection 126 . Also, a lower risk of hypoglycaemia (day and night), especially during the initial titration period is observed with glargine U300 127 .…”