Robust PBPK/PD-Based Model Predictive Control of Blood Glucose

IEEE Trans Biomed Eng. 2016 Jul;63(7):1492-504. doi: 10.1109/TBME.2015.2497273. Epub 2015 Nov 2.


Goal: Automated glucose control (AGC) has not yet reached the point where it can be applied clinically [3]. Challenges are accuracy of subcutaneous (SC) glucose sensors, physiological lag times, and both inter- and intraindividual variability. To address above issues, we developed a novel scheme for MPC that can be applied to AGC.

Results: An individualizable generic whole-body physiology-based pharmacokinetic and dynamics (PBPK/PD) model of the glucose, insulin, and glucagon metabolism has been used as the predictive kernel. The high level of mechanistic detail represented by the model takes full advantage of the potential of MPC and may make long-term prediction possible as it captures at least some relevant sources of variability [4]. Robustness against uncertainties was increased by a control cascade relying on proportional-integrative derivative-based offset control. The performance of this AGC scheme was evaluated in silico and retrospectively using data from clinical trials. This analysis revealed that our approach handles sensor noise with a MARD of 10%-14%, and model uncertainties and disturbances.

Conclusion: The results suggest that PBPK/PD models are well suited for MPC in a glucose control setting, and that their predictive power in combination with the integrated database-driven (a priori individualizable) model framework will help overcome current challenges in the development of AGC systems.

Significance: This study provides a new, generic, and robust mechanistic approach to AGC using a PBPK platform with extensive a priori (database) knowledge for individualization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Blood Glucose* / analysis
  • Blood Glucose* / drug effects
  • Computer Simulation
  • Decision Making, Computer-Assisted
  • Diabetes Mellitus, Type 1 / metabolism
  • Glucagon / analysis
  • Glucagon / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology
  • Insulin / analysis
  • Insulin / metabolism
  • Insulin / pharmacology
  • Models, Biological*
  • Models, Statistical*
  • Monitoring, Physiologic
  • Pancreas, Artificial*
  • Subcutaneous Tissue / chemistry


  • Blood Glucose
  • Hypoglycemic Agents
  • Insulin
  • Glucagon