title: Population pharmacokinetics and pharmacodynamics of IONIS-GCGRRx, an antisense oligonucleotide for type 2 diabetes mellitus: a red blood cell lifespan model.
abstract: IONIS-GCGRRx(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-GCGRRxvia 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 GCGRRxwas 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 Imaxand baseline FPG had a negative correlation with the glycosylation rate (kgl). 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.
authors.affiliation: Clinical Pharmacology, Ionis Pharmaceuticals, Inc., 2855 Gazelle Ct., Carlsbad, CA, 92010, USA. kenneth.t.luu@gmail.com.
authors.forename: Kenneth T
authors.identifier: 0000-0003-4839-5331
authors.initials: KT
authors.lastname: Luu
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Morgan
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bhanot
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Geary
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Smith
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Claudette
authors.initials: C
authors.lastname: Bethune
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Lynnetta
authors.initials: L
authors.lastname: Watts
authors.affiliation: Nonclinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Henry
authors.affiliation: Clinical Pharmacology, Ionis Pharmaceuticals, Inc., 2855 Gazelle Ct., Carlsbad, CA, 92010, USA.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004912:Erythrocytes / Q000187:drug effects*; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D016376:Oligonucleotides, Antisense
keywords: Antisense oligonucleotides; Glucagon receptor; Glucose; HbA1c; Red blood cell lifespan model; Type 2 diabetes mellitus