Population Pharmacokinetics of Exendin-(9-39) and Clinical Dose Selection in Patients with Congenital Hyperinsulinism

Summary

Aims

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycaemia in infants and children. Exendin-(9-39), an inverse glucagon-like peptide 1 (GLP-1) agonist, is a novel therapeutic agent for HI that has demonstrated glucose-raising effect. We reported the first population pharmacokinetic (PopPK) model of the exendin-(9-39) in patients with HI and proposed the optimal dosing regimen for future clinical trials in neonates with HI.

Methods

182 pharmacokinetic (PK) observations from 26 subjects in three clinical studies were included for constructing the PopPK model using FOCE with interaction method in NONMEM. Exposure metrics (area under the curve [AUC] and maximum plasma concentration [C_max]) at no observed adverse effect levels (NOAELs) in rats and dogs were determined in toxicology studies.

Results

Observed concentration-time profiles of exendin-(9-39) were described by a linear two-compartmental PK model. Following allometric scaling of PK parameters, age and creatinine clearance did not significantly affect clearance. The calculated clearance and elimination half-life for adult subjects with median weight of 69 kg were 11.8 L/hr and 1.81 hours, respectively. The maximum recommended starting dose determined from modelling and simulation based on the AUC_0-last at the NOAEL and predicted AUC_0-inf using the PopPK model was 27 mg/kg/day intravenously.

Conclusions

This is the first study to investigate the PopPK of exendin-(9-39) in human. The final PopPK model was successfully used with preclinical toxicology findings to propose the optimal dosing regimen of exendin-(9-39) for clinical studies in neonates with HI, allowing for a more targeted dosing approach to achieve desired glycaemic response.

http://ift.tt/2zU2t69