GCGR
Glucagon receptor precursor (GL-R)
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IONIS-GCGR (ISIS 449884) is an antisense oligonucleotide inhibitor of the glucagon receptor (GCGR). The objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-GCGR via population-based modeling. The observed data were obtained from a Phase 1 (50, 100, 200, 300 and 400 mg) single- and multiple-dose study in healthy volunteers and a Phase 2 (100 and 200 mg) multiple-dose study in T2DM patients. The PK of IONIS GCGR was characterized by two primary systemic compartments and three absorption transit compartments with elimination out of the peripheral compartment. The fasting plasma glucose (FPG) PD was an indirect-response model (inhibition of FPG production) linked to the HbA1c PD model which was a semi-mechanistic model capturing RBC maturation dynamics. Stepwise covariate modeling was performed to identify relevant covariates. In the PK model, bodyweight (BW) was the only significant covariate influencing tissue clearance, tissue volume and plasma volume. Plots of parameter-covariate relations indicate the influence of BW is clinically relevant. In the PD models, baseline HbA1c had a positive correlation with I and baseline FPG had a negative correlation with the glycosylation rate (k ). Simulations from the final model showed that the doses tested in the Phase 2 were at or close to the maximum of the dose-response curve and that dose reduction down to 50 mg resulted in minimal effect to efficacy. The model was useful in supporting the decision for dose reduction in a subsequent trial.
MeSH Terms
- Adolescent
- Adult
- Aged
- Blood Glucose
- Clinical Trials, Phase I as Topic
- Clinical Trials, Phase II as Topic
- Diabetes Mellitus, Type 2
- Dose-Response Relationship, Drug
- Double-Blind Method
- Erythrocytes
- Female
- Humans
- Hypoglycemic Agents
- Male
- Middle Aged
- Models, Biological
- Oligonucleotides, Antisense
- Young Adult
Keywords
- Antisense oligonucleotides
- Glucagon receptor
- Glucose
- HbA1c
- Red blood cell lifespan model
- Type 2 diabetes mellitus