PMID- 29271001
OWN - NLM
STAT- MEDLINE
DCOM- 20190909
LR  - 20221207
IS  - 1532-6535 (Electronic)
IS  - 0009-9236 (Linking)
VI  - 104
IP  - 4
DP  - 2018 Oct
TI  - Development and Qualification of a Drug-Disease Modeling Platform to Characterize 
      Clinically Relevant Endpoints in Type 2 Diabetes Trials.
PG  - 699-708
LID - 10.1002/cpt.998 [doi]
AB  - Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized 
      by persistently elevated blood glucose concentration (hyperglycemia). We 
      developed a mechanistic drug-disease modeling platform based on data from more 
      than 4,000 T2DM subjects in seven phase II/III clinical trials. The model 
      integrates longitudinal changes in clinically relevant biomarkers of glycemic 
      control with information on baseline disease state, demographics, disease 
      progression, and different therapeutic interventions, either when given alone or 
      as add-on combination therapy. The model was able to simultaneously characterize 
      changes in fasting plasma glucose, fasting serum insulin, and glycated hemoglobin 
      A1c following administration of sulfonylurea, metformin, and thiazolidinedione as 
      well as disease progression in clinical trials ranging from 16-104 weeks of 
      treatment. The mechanistic components of this generalized mechanism-based 
      platform, based on knowledge of pharmacology, insulin-glucose homeostatic 
      feedback, and diabetes pathophysiology, allows its application to be further 
      expanded to other antidiabetic drug classes and combination therapies.
CI  - (c) 2017 American Society for Clinical Pharmacology and Therapeutics.
FAU - Gaitonde, Puneet
AU  - Gaitonde P
AD  - Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, 
      University of Florida, Lake Nona (Orlando), Florida, USA.
AD  - Clinical Pharmacology, Global Product Development, Pfizer, Groton, Connecticut, 
      USA.
FAU - Hurtado, Felipe K
AU  - Hurtado FK
AD  - Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, 
      University of Florida, Lake Nona (Orlando), Florida, USA.
FAU - Garhyan, Parag
AU  - Garhyan P
AD  - Global PK/PD & Pharmacometrics, Eli Lilly and Company, Lilly Corporate Center, 
      Indianapolis, Indiana, USA.
FAU - Chien, Jenny Y
AU  - Chien JY
AD  - Global PK/PD & Pharmacometrics, Eli Lilly and Company, Lilly Corporate Center, 
      Indianapolis, Indiana, USA.
FAU - Schmidt, Stephan
AU  - Schmidt S
AD  - Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, 
      University of Florida, Lake Nona (Orlando), Florida, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180201
PL  - United States
TA  - Clin Pharmacol Ther
JT  - Clinical pharmacology and therapeutics
JID - 0372741
RN  - 0 (Biomarkers)
RN  - 0 (Blood Glucose)
RN  - 0 (Glycated Hemoglobin A)
RN  - 0 (Hypoglycemic Agents)
RN  - 0 (Insulin)
RN  - 0 (Sulfonylurea Compounds)
RN  - 0 (Thiazolidinediones)
RN  - 0 (hemoglobin A1c protein, human)
RN  - 9100L32L2N (Metformin)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Biomarkers/blood
MH  - Blood Glucose/*drug effects/metabolism
MH  - Clinical Trials as Topic/*methods
MH  - Diabetes Mellitus, Type 2/blood/diagnosis/*drug therapy
MH  - Dose-Response Relationship, Drug
MH  - Drug Therapy, Combination
MH  - *Endpoint Determination
MH  - Female
MH  - Glycated Hemoglobin/metabolism
MH  - Humans
MH  - Hypoglycemic Agents/adverse effects/pharmacokinetics/*therapeutic use
MH  - Insulin/blood
MH  - Male
MH  - Metformin/therapeutic use
MH  - Middle Aged
MH  - *Models, Biological
MH  - *Research Design
MH  - Sulfonylurea Compounds/therapeutic use
MH  - Thiazolidinediones/therapeutic use
MH  - Time Factors
MH  - Treatment Outcome
EDAT- 2017/12/23 06:00
MHDA- 2019/09/10 06:00
CRDT- 2017/12/23 06:00
PHST- 2017/08/08 00:00 [received]
PHST- 2017/12/14 00:00 [revised]
PHST- 2017/12/17 00:00 [accepted]
PHST- 2017/12/23 06:00 [pubmed]
PHST- 2019/09/10 06:00 [medline]
PHST- 2017/12/23 06:00 [entrez]
AID - 10.1002/cpt.998 [doi]
PST - ppublish
SO  - Clin Pharmacol Ther. 2018 Oct;104(4):699-708. doi: 10.1002/cpt.998. Epub 2018 Feb 
      1.