Pharmacokinetic and Pharmacodynamic Modeling of a Monoclonal Antibody Antagonist of Glucagon Receptor in Male ob/ob Mice

Abstract

Elevated basal concentrations of glucagon and reduced postprandial glucagon suppression are partly responsible for the increased hepatic glucose production seen in type 2 diabetic patients. Recently, it was demonstrated that an antagonistic human monoclonal antibody (mAb) blocking glucagon receptor (GCGR) has profound glucose-lowering effects in various animal models. To further understand the effects on glucose homeostasis mediated by such an antibody, a pharmacokinetic-pharmacodynamic (PK-PD) study was conducted in a diabetic ob/ob mouse model. Four groups of ob/ob mice were randomized to receive single intraperitoneal administration of placebo, 0.6, 1, or 3 mg/kg of mAb GCGR, a fully human mAb against GCGR. The concentration-time data were used for noncompartmental and compartmental analysis. A semi-mechanistic PK-PD model incorporating the glucose-glucagon inter-regulation and the hypothesized inhibitory effect of mAb GCGR on GCGR signaling pathway via competitive inhibition was included to describe the disposition of glucose and glucagon over time. The pharmacokinetics of mAb GCGR was well characterized by a two-compartment model with parallel linear and nonlinear saturable eliminations. Single injection of mAb GCGR caused a rapid glucose-lowering effect with blood glucose concentrations returning to baseline by 4 to 18 days with increasing dose from 0.6 to 3 mg/kg. Elevation of glucagon concentrations was also observed in a dose-dependent manner. The results illustrated that the feedback relationship between glucose and glucagon in the presence of mAb GCGR could be quantitatively described by the developed model. The model may provide additional understanding in the underlying mechanism of GCGR antagonism by mAb.

Therapeutic antibodies directed at G protein-coupled receptors

“…Furthermore, the antibody was evaluated in a diabetic ob/ob mouse model for pharmacokinetic and pharmacodynamic characteristics. 59 The results indicate that such an antibody could represent an effective new therapeutic for the treatment of type 2 diabetes by reducing blood glucose levels and inhibiting GCGR activity.…”

Minireview: Glucagon in the Pathogenesis of Hypoglycemia and Hyperglycemia in Diabetes

“…Additional evidence that glucagon supports the plasma glucose concentration, largely in experimental animals, includes studies with neutralizing glucagon antibodies (74), glucagon antagonists (75)(76)(77)(78)(79), and glucagon receptor antisense oligonucleotides (80 -82), those in glucagon receptor-null (23,83,84) and ␣-cell-deleted (85) mice, and those of the effect of leptin (86 -89). Administration of a neutralizing glucagon antibody has been shown to lower plasma glucose concentrations in several species including nondiabetic and diabetic rabbits (75).…”

“…Administration of a neutralizing glucagon antibody has been shown to lower plasma glucose concentrations in several species including nondiabetic and diabetic rabbits (75). Glucagon antagonists have been reported to lower plasma glucose concentrations in ob/ob mice (76), reduce the blood glucose response to glucagon administration in mice and rhesus monkeys, and lower blood glucose concentrations in mice fed a high-fat diet (77), block the effect of administered glucagon to increase hepatic glucose production in dogs (78), and lower fasting plasma glucose concentrations in mice fed a high-fat diet (79).…”

A Semi-mechanistic Model for the Effects of a Novel Glucagon Receptor Antagonist on Glucagon and the Interaction Between Glucose, Glucagon, and Insulin Applied to Adaptive Phase II Design

“…Another model describing the feedback relationship between glucose and glucagon in the presence of a monoclonal antibody antagonist of glucagon receptor in mice was developed, but insulin was not collected and incorporated in the model due to the limitation of maximum volume of blood collection (14). Recently, an integrated glucose-insulin-glucagon model was published for an oral glucokinase activator (15).…”