Dose Rationale of Nasal Glucagon in Japanese Pediatric Patients with Diabetes Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation.

Abstract

Nasal glucagon (NG) 3 mg is approved in Japan to treat hypoglycemia in pediatric patients with diabetes, but an NG clinical study has not been performed in Japanese children because of practical and ethical concerns. The aim of this study is to support the dose rationale for NG 3 mg in Japanese pediatric patients with diabetes using modeling and simulation. We used a pharmacokinetic/pharmacodynamic bridging approach to extrapolate the available clinical data to Japanese pediatric patients. Population pharmacokinetic/pharmacodynamic modeling was performed using data from seven clinical studies, including five studies in non-Japanese adults, one study in Japanese adults, and one study in non-Japanese pediatric patients. Simulation was then used to estimate glucagon exposure and glucose response after NG 3-mg administration for three age categories of Japanese pediatric patients: 4 to <8, 8 to <12, and 12 to <18 years. Treatment success was defined as an increase in blood glucose to ≥70 or ≥20 mg/dL from nadir within 30 min after administration of NG 3 mg. Safety was assessed in relation to the predicted maximum glucagon concentration of NG 3 mg using NG clinical trial data and published data on intravenous and intramuscular glucagon. The data showed a rapid and robust glucose response following NG 3 mg in Japanese and non-Japanese adults and non-Japanese pediatric patients, with some differences in glucagon exposure observed across studies. The pharmacokinetic/pharmacodynamic model described the observed clinical data well, and simulations indicated that >99% of hypoglycemic Japanese pediatric patients in all three age groups would achieve treatment success. Predicted glucose responses to NG 3 mg in Japanese pediatric patients were comparable to those of intramuscular glucagon. Maximum concentration was not associated with the occurrence and severity of common adverse events (nausea, vomiting, and headache) in NG clinical studies. Furthermore, the predicted maximum concentration in Japanese pediatric patients, despite being higher than the observed maximum concentration in NG clinical studies, was substantially lower than the observed maximum concentration of 1 mg of intravenous glucagon, without serious safety issues. This analysis suggests NG 3 mg has robust efficacy without serious safety concerns in Japanese pediatric patients with diabetes.