Single‐dose pharmacokinetics and glucodynamics of the novel, long‐acting basal insulin LY2605541 in healthy subjects

Abstract

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.

LY2605541—A Preferential Hepato-Specific Insulin Analogue

“…LY2605541 has a T max after 18-42 h and a T½ of 24-45 h compared with 10-12 and 12-15 h for insulin glargine (8). The T½ increased from about 35 h in patients with normal kidney function to about 46 h in patients with end-stage renal disease (9).…”

New Long-Acting Basal Insulins: Does Benefit Outweigh Cost?

“…2), thereby increasing the hydrodynamic size of the insulin-PEG complex (1,3,4,15,20,21,(45)(46)(47)(48). PegLispro has an even lower binding affinity for both the insulin receptor and IGF-1 receptor than lispro and a lower mitogenic potency than human insulin (45,47,48).…”

“…2), thereby increasing the hydrodynamic size of the insulin-PEG complex (1,3,4,15,20,21,(45)(46)(47)(48). PegLispro has an even lower binding affinity for both the insulin receptor and IGF-1 receptor than lispro and a lower mitogenic potency than human insulin (45,47,48). It possesses a prolonged duration of action exceeding 36 h as a result of delayed absorption and reduced clearance, with a low intrasubject variability in glucose lowering and a lower and quite different tissue distribution compared with the other insulin preparations (45,47,48).…”

“…PegLispro has an even lower binding affinity for both the insulin receptor and IGF-1 receptor than lispro and a lower mitogenic potency than human insulin (45,47,48). It possesses a prolonged duration of action exceeding 36 h as a result of delayed absorption and reduced clearance, with a low intrasubject variability in glucose lowering and a lower and quite different tissue distribution compared with the other insulin preparations (45,47,48). Both animal and human studies suggested that PegLispro may have a preferential hepato-specific action on glucose metabolism compared with insulin glargine (49).…”

Lower Glucose Variability and Hypoglycemia Measured by Continuous Glucose Monitoring With Novel Long-Acting Insulin LY2605541 Versus Insulin Glargine

“…Administration of LY2605541 produces a long, flat pharmacodynamic profile with small peak-to-trough fluctuations with a half-life of 2-3 days. LY2605541 demonstrated reduced pharmacokinetic variability, suggesting the potential for less glycemic variability and hypoglycemia (13,14). Therefore, in a predefined substudy in a phase II clinical trial comparing LY2605541 treatment with insulin glargine (GL) in patients with type 2 diabetes, CGM was performed in an investigator-selected cohort of patients to permit a more detailed description of 24-h glycemia, which potentially may include unrecognized hypoglycemia.…”