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Dose selection using a semi-mechanistic integrated glucose-insulin-glucagon model: designing phase 2 trials for a novel oral glucokinase activator

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Abstract

Selecting dosing regimens for phase 2 studies for a novel glucokinase activator LY2599506 is challenging due to the difficulty in modeling and assessing hypoglycemia risk. A semi-mechanistic integrated glucose-insulin-glucagon (GIG) model was developed in NONMEM based on pharmacokinetic, glucose, insulin, glucagon, and meal data obtained from a multiple ascending dose study in patients with Type 2 diabetes mellitus treated with LY2599506 for up to 26 days. The series of differential equations from the NONMEM model was translated into an R script to prospectively predict 24-h glucose profiles following LY2599506 treatment for 3 months for a variety of doses and dosing regimens. The reduction in hemoglobin A1c (HbA1c) at the end of the 3-month treatment was estimated using a transit compartment model based on the simulated fasting glucose values. Two randomized phase 2 studies, one with fixed dosing and the other employing conditional dose titration were conducted. The simulation suggested that (1) Comparable HbA1c lowering with lower hypoglycemia risk occurs with titration compared to fixed-dosing; and (2) A dose range of 50–400 mg BID provides either greater efficacy or lower hypoglycemia incidence or both than glyburide. The predictions were in reasonable agreement with the observed clinical data. The model predicted HbA1c reduction and hypoglycemia risk provided the basis for the decision to focus on the dose-titration trial and for the selection of doses for the demonstration of superiority of LY2599506 to glyburide. The integrated GIG model represented a valuable tool for the evaluation of hypoglycemia incidence.

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Abbreviations

ka:

Absorption rate constant

CL/F:

Apparent clearance

V/F:

Apparent volume of distribution

BMI:

Body mass index

CFB:

Change from baseline

FPG:

Fasting plasma glucose

GIG:

Glucose-insulin-glucagon

GK:

Glucokinase

GKA:

Glucokinase activator

HbA1c:

Hemoglobin A1c

LOCF:

Last observation carried forward

LC–MS/MS:

Liquid chromatography/tandem mass spectrometry

MAD:

Multiple ascending dose

M&S:

Modeling and simulation

PopPK:

Population PK

PPG:

Postprandial glucose

RBC:

Red blood cell

SMBG:

Self-monitored blood glucose

SUs:

Sulfonylureas

T2DM:

Type 2 diabetes mellitus

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Acknowledgments

The authors thank the entire Lilly GKA team for making the clinical data available.

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Authors and Affiliations

  1. Global PK/PD/Pharmacometrics, Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, 46285, USA

    Xin Zhang, Karen Schneck, Juliana Bue-Valleskey, Kwee Poo Yeo, Michael Heathman & Vikram Sinha

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  1. Xin Zhang
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  2. Karen Schneck
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  3. Juliana Bue-Valleskey
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  5. Michael Heathman
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  6. Vikram Sinha
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Correspondence to Xin Zhang.

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Zhang, X., Schneck, K., Bue-Valleskey, J. et al. Dose selection using a semi-mechanistic integrated glucose-insulin-glucagon model: designing phase 2 trials for a novel oral glucokinase activator. J Pharmacokinet Pharmacodyn 40, 53–65 (2013). https://doi.org/10.1007/s10928-012-9286-9

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  • DOI: https://doi.org/10.1007/s10928-012-9286-9

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