title: Simple pharmacometric tools for oral anti-diabetic drug development: competitive landscape for oral non-insulin therapies in type 2 diabetes.
abstract: The objectives were to develop a translational model that will help select doses for Phase-3 trials based on abbreviated Phase-2 trials and understand the competitive landscape for oral anti-diabetics based on efficacy, tolerability and ability to slow disease progression. Data for eight anti-diabetics with temporal profiles for fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) from 12 publications were digitized. The monotherapy data consisted of FPG and HbA1c profiles that were modeled using a transit compartment model. Evaluation of the competitive landscape utilized HbA1c literature data for 11 drugs. For the safety metric, tolerability issues with anti-diabetic drug classes were tabulated. For disease progression, the coefficient of failure method was used for assessing data from two long-term trials. The transit rate constants were remarkably consistent across 12 trials and represent system-specific/drug-independent parameters. The competitive landscape analysis showed that the primary efficacy metric fell into two groups of DeltaHbA1c: >0.8% or approximately 0.8%. On the safety endpoints, older agents showed some tolerability issues while the new agents were relatively safe. Among the different drug classes, only the thiazolidinediones appeared to slow disease progression but may also increase heart failure risk. In conclusion, the ability of system-specific parameters to predict HbA1c provides a tool to predict the expected efficacy profile from abbreviated dose-finding trials. To be commercially viable, new drugs should improve DeltaHbA1c by about 0.8% or more and possess safety profiles similar to newer anti-diabetic agents. Thus, this study proposes a suite of simple yet powerful tools to guide type-2-diabetes drug development.
authors.affiliation: Clinical Pharmacology-Advanced PK/PD Modeling and Simulation, Johnson & Johnson Pharmaceutical Research & Development, Raritan, New Jersey 08869, USA. msamtani@its.jnj.com
authors.forename: Mahesh N
authors.initials: MN
authors.lastname: Samtani
mesh_terms: D000284:Administration, Oral; D001786:Blood Glucose; D017326:Clinical Trials, Phase III as Topic; D017281:Cost of Illness; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D018450:Disease Progression; D004334:Drug Administration Schedule; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D010349:Patient Compliance; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin