Population pharmacokinetics and pharmacodynamics of nasal glucagon in patients with type 1 or 2 diabetes

Abstract

The objective was to characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of glucagon after injectable or nasal administration and confirm the appropriate therapeutic dose of nasal glucagon (NG) for adult patients. Six clinical studies with PK and five clinical studies with PD (glucose) data were included in the analysis. Doses ranging from 0.5 to 6 mg NG, and 0.5 to 1 mg injectable glucagon were studied. A total of 6284 glucagon and 7130 glucose concentrations from 265 individuals (patients and healthy participants) were available. Population PK/PD modeling was performed using NONMEM. Glucagon exposure and glucose response were simulated for patients administered various doses of NG to confirm the optimal dose. Glucagon PK was well-described with a single compartment disposition with first-order absorption and elimination processes. Bioavailability of NG relative to injectable glucagon was 16%. Exposure–response modeling revealed that lower baseline glucose was associated with higher maximum drug effect. The carry-over effect from prior insulin administration was incorporated into the model through a time-dependent increase in elimination rate of glucose. Simulations showed that more than 99% of hypoglycemic adult patients would experience treatment success, defined as an increase in blood glucose to ≥70 mg/dL or an increase of ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. The population PK/PD model adequately described the PK and PD profiles of glucagon after nasal administration. Modeling and simulations confirmed that NG 3 mg is the most appropriate dose for rescue treatment during hypoglycemia emergencies.