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7, JULY 2016
Robust PBPK/PD-Based Model Predictive
Control of Blood Glucose
Stephan Schaller∗ , Jörg Lippert, Lukas Schaupp, Thomas R. Pieber, Andreas Schuppert, and Thomas Eissing
Abstract—Goal: Automated glucose control (AGC) has not yet
reached the point where it can be applied clinically [3]. Chal-
lenges are accuracy of subcutaneous (SC) glucose sensors, phys-
iological 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 mecha-
nistic 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]. Robust-
ness against uncertainties was increased by a control cascade rely-
ing on proportional-integrative derivative-based offset control. The
performance of this AGC scheme was evaluated in silico and retro-
spectively 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 sug-
gest that PBPK/PD models are well suited for MPC in a glucose con-
trol setting, and that their predictive power in combination with the
integrated database-driven (a priori individualizable) model frame-
work 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.
Index Terms—Artificial pancreas (AC), decision support, dia-
betes, glucose metabolism, patient variability, physiology-based
pharmacokinetics and pharamcodynamics (PBPK/PD), predictive
control, predictive models.
I. INTRODUCTION
IABETES mellitus is a chronic disease that affects a
D continuously growing population of currently over 380
Manuscript received May 20, 2014; revised April 7, 2015, June 7, 2015, and
September 15, 2015; accepted October 27, 2015. Date of publication November
2, 2015; date of current version June 16, 2016. The work of S. Schaller, J.
Lippert, L. Schaupp, T. R. Pieber, and T. Eissing was supported in part by
the European Commission under Grant Agreement 248590 (FP7 Integrated
Project Reaction; Remote Accessibility to Diabetes Management and Therapy
in Operational Healthcare Networks). Asterisk indicates corresponding author.
* S. Schaller is with the Department of Computational Systems Biology,
Bayer Technology Services GmbH, Leverkusen 51368, Germany, and also with
the Aachen Institute for Advanced Study in Computational Engineering Sci-
ences, RWTH Aachen, Aachen 52062, Germany (e-mail: stephan.schaller@
rwth-aachen.de).
J. Lippert is with the Department of Computational Systems Biology, Bayer
Technology Services GmbH, and also with Clinical Pharmacometrics, Bayer
Pharma AG.
L. Schaupp and T. R. Pieber are with the Department of Internal Medicine,
Medical University of Graz
A. Schuppert is with the Department of Computational Systems Biology,
Bayer Technology Services GmbH, and also with the Aachen Institute for
Advanced Study in Computational Engineering Sciences, RWTH Aachen
T. Eissing is with the Department of Computational Systems Biology, Bayer
Technology Services GmbH
Color versions of one or more of the figures in this paper are available online
at http://ieeexplore.ieee.org.
Digital Object Identifier 10.1109/TBME.2015.2497273
0018-9294 © 2015 IEEE. Translations and content mining are permitted for academic research only. Personal use is also permitted, but republication/redistribution
requires IEEE permission. See http://www.ieee.org/publications standards/publications/rights/index.html for more information.
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO.
million patients worldwide [5]. Type-2 diabetes (T2DM) ac-
counts for 85% to 95% of all diabetes. It is caused by a defect
in the body’s autonomous regulation of blood glucose, which
is normally managed by complex interactions among neuronal,
hormonal, and metabolic-signaling networks. Type-1 diabetes
(T1DM), although less common, has a high prevalence in chil-
dren and adolescents and is caused by an autoimmune reaction
damaging the insulin producing beta cells of the pancreas. Cur-
rently, T1DM and severe cases of T2DM can only be controlled
by the affected individual, through constant vigilance and man-
ual insulin therapy.
Effective automated control of blood-glucose levels could
theoretically reduce the burden of manual therapy and improve
the risk profiles of most patients with T1DM. Additional ben-
efits would include improved quality of life and reduced costs
[6]. An integrated system that combines a subcutaneously (SC)
implanted continuous glucose monitor (CGM) and an insulin in-
fusion pump (IIP) are often referred to as an “artificial pancreas”
(AP).
Although AP systems have been under development for more
than 50 years, they are still not capable of orchestrating every-
day control of blood glucose. This is due to both technical and
system-inherent hurdles, including: 1) insufficient accuracy of
CGM devices, 2) the lag times of SC glucose measurements
(SCGM) when changes in blood-glucose levels are rapid, 3 the
lag time for the onset of insulin action after SC insulin adminis-
tration, and 4) the lingering/tailing action of insulin action after
SC administration [3], [7], [8].
Recent improvements in the accuracy of SC CGM devices,
IIPs, and safety systems have enhanced conditions for develop-
ing a fully integrated AP system [8], [9]. Also, the superiority
of AGC involving both SC measurement of glucose and SC
infusion of insulin (the SC–SC route) over manual control of
glucose levels has been demonstrated in clinical trials [10].
Various strategies for controlling blood glucose, ranging from
proportional-integrated derivative (PID) [11]–[17] to complex
fuzzy logic methods [18], [19], have been used in designs for the
AP. Nevertheless, physiologic lag times remain a core problem
in reactive (i.e., PID) feedback-control solutions [20]. These lag
times are better addressed using predictive control solutions,
and model predictive control (MPC) is the most widely used
among these [21]–[27].
Key components of such MPC approaches are mathematical
models of the biological processes relevant to glucose control.
Early models only vaguely reflected the physiological structures
involved, in spite of the fact that these are vital to comprehend-
ing the influence of lag times. Research to improve these models
focused on more physiology-based model concepts, as model-
based glucose control requires reliable models with longer term
SCHALLER∗ et al.: ROBUST PBPK/PD-BASED MODEL PREDICTIVE CONTROL OF BLOOD GLUCOSE
predictive capabilities. Recently, the UVa/Padova simulator,
which is based on a model by Dalla Man et al. [28], proved suffi-
ciently effective to receive approval from the U.S. Federal Drug
Administration as a replacement for animal testing of glucose
controllers [29]. In addition, the Cambridge Model developed
by Hovorka et al. [30] for closed-loop glucose control incorpo-
rates physiological aspects and represents the current state of
the art in glucose modeling as it applies to model-based glucose
control. However, even these more physiological models fail to
scale key parameters such as blood flow, organ volume, and sub-
compartment size to an individual’s anthropologic properties. A
fully physiological modeling framework such as that described
in [4] allows for a priori individualization of these properties of
the model with respect to age, weight, height, gender, and race.
We have developed a control approach that combines, for
the first time, a detailed a priori individualizable generic
whole-body physiology-based pharmacokinetic and dynamics
(PBPK/PD) model of the glucose-insulin metabolism (GIM)
[4] with a robust MPC algorithm for AGC in a post hoc in sil-
ico study. Based on this accurate model for predicting the core
dynamics of blood-glucose levels (i.e., in the undisturbed state)
in an individual and adapting over time by adding continuously
gathered patient data, the MPC computes an optimal feedfor-
ward control input. To increase closed-loop stability as well as
robustness against both disturbances and model uncertainties,
we use a PID-based feedback controller that compensates for
prediction errors (offset).
Here we test, in silico, the performance of the control algo-
rithm in a simulated control trial, in the face of measurement
error, model uncertainty, and disturbances.
II. MATERIALS AND METHODS
The glucose control framework developed here allows both
in silico evaluation of controller concepts and control of blood
glucose in T1DM patients in a clinical setting. The interac-
tions among the components of the integrated system are based
on the modular approach described in [8]. The three interact-
ing layers work on different timescales (see Appendix Fig. 5).
The outer layer is on a slow timescale and adjusts the param-
eters of the inner fast layer. In the system described here, the
outer layer is represented by model adaptation, i.e., “offline op-
timization,” using glucose measurement data to adjust the model
kernel of the MPC (middle layer). The MPC, i.e., “online sim-
ulation and control,” in turn, calculates insulin delivery based
on the prediction of blood-glucose levels and meal information.
The middle layer is further restricted by the inner layer, i.e.,
the robustness layer, which is comprised of the offset-controller
(PID). It constantly adjusts 1) the blood-glucose target value
for the MPC and 2) the insulin doses calculated by the MPC.
The insulin adjustments are based on the latest CGM data (and
the predictive error), incorporating algorithms for pump shutoff,
and insulin-on-board constraints.
Once the integrated system is in place, various increasingly
complex configurations of an AP system become possible.
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A. Individualized Physiology-Based Models and Software
PBPK models describe the mechanisms underlying the ab-
sorption, distribution, metabolism, and excretion of a substance
within the body in great detail. Such models are based to a large
extent on prior information. This information is taken from col-
lections of anatomical and physiological data, and calculations
are made based on the drug’s physiochemical properties and
their effects on various organs and tissues, taking into account
an organism’s anatomy and physiology and its changes with
age, as well as its weight, height, gender, and race (e.g., age de-
pendence of organ weights, blood flows). Also, the information
about how active processes (e.g., metabolic rates, transport, and
clearance rates) scale with relation to these properties is inte-
grated. Generic adult PK prediction models can automatically
be parameterized based on the basic physicochemical param-
eters of a substance, and can then be used to simulate drug-
concentration profiles in various organs and tissues [31]. Once
an adult PBPK model has been established, it can be extrapo-
lated to individuals—be it adults, children, or elderly—outside
of the selected cohort [32]. The PBPK models for glucose, in-
sulin, and glucagon [4] were established in the PK-Sim 5.1,
and coupled in the MoBi 3.1, commercial software packages
for PBPK modeling and molecular biology modeling, respec-
tively [1], [31]. Model identification, model parameterization,
and the development of control algorithms were conducted us-
ing the MoBi Toolbox for MATLAB 3 and MATLAB 2012 (The
MathWorks, Natick, MA, USA).
B. Generating Virtual Patients
The model used to generate the in silico subjects in the sim-
ulation environment was previously described in detail and val-
idated, including how the parameters for the generic model
were set [4]. This model was fitted to a dataset collected for
12 T1DM patients studied in a 2-phase randomized crossover
trial (2PRCT, from the project Advanced Insulin Infusion using
a Control Loop [33], and the effectiveness of continuous SC
insulin infusion was compared to that of an MPC system (Cam-
bridge Algorithm [33])), generating 12 virtual patients. In the
absence of SC glucagon infusion and mean meal-independent
parameters for oral glucose absorption, the algorithm identifies
six parameters (first six in Table II, Appendix) for model indi-
vidualization (also in [4], supporting information Table S3) from
the blood-glucose measurement data, and then fits the generic
model to the respective patient data to generate a virtual patient.
Thus, the in silico subjects used for the in silico validation and
the MPC algorithm presented here use the exact same model as
presented in [4]. The models may only differ by their physio-
logic values (e.g., physiology-dependent (calculated) properties
like blood volume) and the six identified parameters used for
model individualizations (the MPC is initialized with mean pop-
ulation values for these six parameters).
To parameterize the model, the fmincon function of the MAT-
LAB optimization toolbox was used with a quadratic penalty
function.
1494
C. Design of In Silico Clinical Trial
The in silico trials evaluating the integrated algorithms were
carried out using the protocol described above for the 2PRCT.
The control inputs used were constant insulin infusions over
15 min, corresponding to the sampling time for blood-glucose
values and CGM readouts (note that although CGM readouts
were taken every 5 min, due to the need for manual handling
every third readout was deemed sufficient). In the 2PRCT proto-
col, the subjects were admitted to the clinical research center at
the Medical University of Graz (MUG) at 2 p.m. Prior to the first
meal on the day of arrival, from 2 p.m. until 5 p.m. (t = 0–180
min), the study started with a glucose clamp and subjects were
adjusted to 100 mg/dl blood glucose and received basal insulin
via a pump until closed-loop control was initiated following the
first meal. Over the course of the trial, the subjects (N = 12) re-
ceived four meals. Dinner (the first meal) was provided at 6 p.m.
(t = 240 min), and closed-loop glucose control was initiated at
7:30 p.m. (t = 330 min, end of observation phase) and contin-
ued until 10 p.m. the following day. On the second day, the
subjects received meals at 7 a.m. (t = 1020 min, breakfast), 12
p.m. (t = 1320 min, lunch), and 6 p.m. (t = 1680 min, dinner).
Meal information was transferred to the controller at the time of
meal onset, such that prandial insulin was not infused prior to
the meals.
The target range for insulin was defined as 70—180-mg/dl 3-h
postprandial and 70–140 mg/dl at all other times. “OVERALL”
refers to the duration of the trial (7:30 p.m., Day 1 to 10 p.m., Day
2), “DAYTIME” to the time from the end of breakfast to the end
of trial (8 a.m., Day 2 to 10 p.m., Day 2), and “OVERNIGHT”
to the nighttime period during the trial (10 p.m., Day 1 to 8 a.m.,
Day 2). Throughout the trial, the control input was calculated
every 15 min, when the blood glucose was sampled.
D. Control Algorithm
The effectiveness of model-based glucose control algorithms
depends on the model kernel being tuned to the system it con-
trols. In the case of blood-glucose control, the model is tuned for
each patient using experimental data gathered over time [12].
The study described here tests our robust MPC algorithm in
an in silico trial, using the protocol described above. During this
trial, glucose measurements from simulated virtual patients were
used to individualize the kernel on which the MPC operates.
The algorithm first establishes a mean model of GIM, and this
is then scaled based on the physiologic properties (age, weight,
height, gender, and race) of the enrolled patient. Model individu-
alization is started with the first blood-glucose measurement at 2
p.m. on Day 1. As the efficient use of time for model individual-
ization (finding a timely solution to the optimization problem) is
paramount, a virtual population was generated a priori based on
the known physiologic properties (e.g., age, weight, and height)
of the patient, but with variations the individual parameter set
(first six parameters in Table II, Appendix) taken from distri-
butions precalculated based on known model parameterizations
[4]. The resulting virtual population was then screened for the
best fit to data collected during the clamp phase (observation
phase), i.e., from 2 p.m. until 7:30 p.m. on the first day. The
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO. 7, JULY 2016
best-fit parameter set was used to initiate the MPC at 7:30 p.m.,
with the optimal insulin dose, uM PC (t) , calculated based on
predictions of the model (see Appendix Fig. 5).
The AGC continuously improves the model kernel used by
the MPC over the course of the trial, as more data becomes
available. The individual parameter set is constantly optimized
based on all measurement data collected up to that point. A
“growing horizon estimatior” (see Appendix Fig. 7) is used to
this end.
However, this feature was deactivated for the purposes of the
in silico analysis described here. The evaluation of controller
performance in the context of suboptimal fit of the model, i.e.,
in the presence of model uncertainty, required that the model
was not adapted following the initial matching. This initially
matched model is suboptimal in the sense that the match from
the initial population is based on a coarse grid search over the
range of the parameters, and does not necessarily reflect the
optimal parameters for the individual.
The algorithm, which was run on a standard laptop PC, was
implemented in MATLAB and controlled via a graphical user
interface (GUI using MATLAB GUIDE). For model adapta-
tion and input optimization, we use the functions fmincon and
fminbnd, respectively, of the MATLAB optimization toolbox.
The parameters used to configure the controller are provided in
Table III (Appendix).
1) Model Predictive Control: MPC is a form of control in
which the “current” control action is determined by solving,
at each sampling instant, a finite-horizon open-loop optimal
control problem P (x, k). A schematic of the general concept
is shown in Appendix Fig. 7. Optimization of the cost function
V (x, k, u) at time k = tk , subject to any imposed control, state,
and terminal constraints, yields an optimal control sequence u of
N piecewise constant control inputs, and the first control in this
sequence at time k = tk is applied to the controlled system [2],
[34]. This produces a closed-loop control strategy, solving an
open-loop optimization problem. The general control problem
is defined as
P (x, k) = min V (x, k, u) (1)
u
with the discretized point in time tk , and the general cost func-
tion
k
+N
V (x, k, u) = l (xi , ui ) + F (xk +N ) (2)
i=k
with stage cost l, the optimized input sequence u =
{uk , uk +1 , . . . , uk +N −1 }, system state xi [corresponds to ei-
ther plasma (IV) glucose or SC glucose], and terminal cost
F (xk +N ).
However, this is a multidimensional optimal control prob-
lem that uses a sequence of piecewise constant inputs u =
{uk , uk +1 , . . . , uk +N −1 }, and, thus, solving it may become
computationally demanding. A common approach to save com-
putational time and increasing the speed of convergence of the
optimization problem is to restrict optimization to the first input
SCHALLER∗ et al.: ROBUST PBPK/PD-BASED MODEL PREDICTIVE CONTROL OF BLOOD GLUCOSE
of the sequence. The cost function is then defined as
k
+N
V (x, k, u) = l (xi ) + uk
i=k
yielding the feedback control law
u0 = u0k .
2) Offset-Control/Error Compensation (PID): To increase
the robustness of the chosen MPC AGC approach, we use
a PID-based offset controller here. The development of such
a controller is based on the basic concepts of feedback con-
trol [35], [36]. In general, a PID controller is based on three
characteristics of the output tracking error e (t) in relation to
a (constant) target value: the weighted current absolute error
(proportional component, P); the weighted sum of all past er-
rors (integral component, I); and the weighted change in error
compared to the error at the last sampling point (derivative com-
ponent, D). These three components are summed in calculating
the control input (see Appendix Fig. 5).
The offset controller is introduced for two reasons: to compen-
sate for inaccuracies of the model fit and to reject disturbances.
Even a detailed PBPK/PD model does not fully account for all
dynamics that may cause an observed change in blood-glucose
levels. The offset controller filters the residual error of the model
predictions made by the MPC (see Appendix Fig. 5). Thus, the
tracking error e (t) corresponds to a prediction error and is cal-
culated as deviation of the simulated blood-glucose prediction,
x (t), from the actual blood-glucose measurements, y (t) (for
more details on simulated concentrations see Appendix A).
Based on these values, the offset-controller calculates two cor-
rections via a feedback loop based on the prediction error e (t).
The first is the set-point correction ΔTV (i.e., a shift in target
value) of the MPC. The second is the control input correction,
Δu (t) , which corrects the insulin infusion recommendations
uM PC (t) made by the MPC.
To increase the robustness of offset control against sensor
noise and disturbances, the fading memory principle from fad-
ing memory proportional derivative control (FMPD) [12–15]
was adapted for the P and D components. The reason a dynamic
target value correction, ΔTV, is used is that in spite of model
inaccuracy (i.e., a model drift), most of the insulin input will be
calculated by the MPC rather than by the feedback controller.
This is to ensure timely control action, as the MPC is a (feedfor-
ward) predictive controller, and shifting influence to the reactive
FMPD feedback component (i.e., the input correction Δu (t))
as the determinant of input would lead to a reduction in overall
response time.
ΔTV is calculated from the relative prediction error
e (t) = x (t) − y (t), such that DynamicTV = TV + ΔTV
and ΔTV (t = 0) = 0. In the context of fading memory, this
gives
 t  t
−W p (t−τ )
ΔTV = Kp e e (τ ) dτ + Ki e (τ ) dτ
0 0
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k 
k
−W p (k −j )
≈ Kp e ej + Ki ej (5)
j =0 j =0
(3)
with the controller gains K and the forgetting factor Wp , in the
case of the proportional component, where Wp determines how
rapidly past values fade from memory. We chose to use an expo-
nentially decaying fading function. The derivative component
(4) was not included in calculating ΔTV, as this would increase the
influence of sensor noise. The integral component was included
to accommodate for the effects of model nonlinearity, ensuring
that the set-point (dynamic target value) error would be zero.
A drawback of dynamic shifting of the target value is that it
could lead to a nonlinear behavior of some components of the
GIM model. This could “distort” the estimate of the insulin dose
required, due to nonlinearities inherent to the model. However,
individualization of the model kernel ultimately reduces the
required shift, diminishing the influences of nonlinearities. The
reason for using only the proportional and integral components
in calculating ΔTV is that this value should compensate solely
for the overall drift in predictive error; short-term deviations and
disturbances are corrected by the input correction, in particular
by its derivative component.
The second component, Δu (t), of the offset controller cor-
rects the input MPC dose calculations, uM PC (t). The calcula-
tion of this error also takes into account the shift in target value
for the MPC controller, correcting only any remaining devia-
tions. This prediction error of ê (t) = ΔTV − e (t) takes into
consideration the dynamic shift ΔTV of the MPC such that the
input correction Δu (t) approaches zero once the target value
is shifted by the value of the prediction error (e (t) = ΔTV). A
generalized formulation of the FMPD control for the calculation
of the input correction Δu (t) is

k 
k
Δuk = Kp e−W p (k −j ) êj + Ki êj
j =0 j =0

k
+Kd e−W d (k −j ) (êj − êj −1 ) . (6)
j =0
The input correction was tuned to respond more rapidly to
changes in e (t). The tuning of the forgetting factors Wp and
Wd within a real control setting is always a tradeoff between
susceptibility to sensor error/noise and an increase in time delay
or “sluggishness” of the controller. As the derivative component
represents the rapid first-response characteristic of a beta cell, a
larger factor (and thus faster memory decay) was chosen.
Both MPC (penalty function) and offset control are sub-
ject to additional safety constraints and parameterizations, as
documented in the Appendix.
Although our results indicate that the MPC control algorithm
is robust even in the context of significant prediction error, a key
feature is that when the model kernel is used in a clinical-trial
setting it will be continuously updated as new measurements
become available. A standard optimization routine (fmincon,
MATLAB) was chosen for optimizing the individual parameter
set [4] in this context.
1496
Fig. 1. Effects of model uncertainty on glucose concentration, insulin in-
fusion, and insulin concentration. Representative in silico run, carried out for
Subject 08. In plots of glucose (top) and insulin (bottom) concentrations (C.), red
triangles represent (simulated) measurements from the in silico individual, and
blue curves represent predictions made by the model. In plot of insulin infusion
(Inf.; centre), blue bars represent doses calculated by the MPC, with green being
the component added by the offset controller, and red the component subtracted
by the offset controller. The target value (TV) for the blood-glucose concentra-
tion was 110 mg/dl. DynamicTV = TV + ΔTV. Light and darker purple
backgrounds indicate an extended (70–180 mg/dl and tight (70–140 mg/dl) glu-
cose target range. The black broken vertical line (t = 330 min) represents start
of control. Only carbohydrates (meals; IV and oral glucose) and insulin during
clamping (prior to t = 330 min) were administered based on the original pro-
tocol of the clinical trial. Information on carbohydrate intake was passed to the
controller upon start of intake, except for extra orange juice (12 g) on day 2 (4
p.m., t = 1560 min). The optimal insulin dose was calculated by the controller.
More details on control performance are given in Tables I and II and Fig. 4.
E. Method for In Silico Controller Evaluation
We have tested our control system against 12 in silico in-
dividuals, with the model parameterized based on the 2PRCT
data. We evaluated the robustness of the controller in the setting
of three potential sources of variability: 1) model uncertainties,
using a suboptimal fit of the internal MPC model kernel; 2) dis-
turbances, e.g., the unanticipated intake of carbohydrates; and
3) sensor error, e.g., simulating sensor noise of both intravenous
(IV) and SCGMs.
For the MPC algorithm, a prediction horizon of N = 240
min (6 h) was chosen. The dose of insulin, which was infused at
constant rate over a 15 min period, was calculated by solving the
nonlinear constrained optimization problem described in (1).
The in silico trials for evaluating the integrated algorithms
were carried out using the same protocol as in the 2PRCT.
As mentioned in Section II-D2, we did not adapt the model
following the initial matching with the starting population.
Given that this study was carried out in preparation for in
vivo clinical trials, we evaluated two scenarios—one in which
IV measurement of glucose was simulated, and another in which
CGM (SC) measurement of glucose was simulated.
The first scenario is for controller evaluation using simulated
IV measurements of glucose with a mean standard deviation
of 5%. This case was used to simulate the Super GL 2 instru-
ment (Dr. Müller Gerätebau GmbH, Freital, Germany; expected
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO. 7, JULY 2016
Fig. 2. Effects of disturbances on glucose concentration, insulin infusion, and
insulin concentration. Representative in silico run, carried out for Subject 06.
Symbols and conditions of experiment are as described for Fig. 1.
measurement error for such measurements is <2% [37]) as it
will be used for IV measurments (for safety reasons) in the first
clinical trial at MUG.
In the second scenario, simulated SCGMs from CGM devices
were used to simulate, e.g., the Dexcom G4 Platinum CGM de-
vice (with mean absolute relative error (MARE) of 10.8 ± 9.9%
[38]), as it will be used in the second clinical trial to evaluate the
performance in a state-of-the-art setting. The simulated noise
for the CGM sensor is documented in the appendix (15).
In addition, a retrospective validation of the controller was
conducted offline. Here, the same protocol was used, but actual
measurements from the 2PRCT trial were used instead of those
from the in silico patients.
III. RESULTS
In silico evaluation is used to verify and validate closed-loop
control algorithms, and is a prerequisite for in vivo testing of
AP systems during clinical trials [29]. This approach provides
valuable information about controller performance (with respect
to both safety and limitations) and is useful in optimizing the
clinical study design.
A. In Silico Evaluation of Online Controller (IV Measurement
of Glucose)
1) Effects of Model Uncertainties: The glucose control al-
gorithm relies on an accurate internal model of the controlled
subject, because inaccurate parameterizations can lead to mis-
calculation of insulin doses by the MPC component. To assess
the implications of model uncertainty, we deactivated model
adaptation and deliberately conducted our in silico evaluation
based on the initial matches of model parameterization that
took place during the clamp phase. Also, the parameters that
affect meal absorption and result in the highest interoccasion
variability within the model (caloric content, fraction solid, and
meal volume [4]) were changed at each meal, with the maximal
SCHALLER∗ et al.: ROBUST PBPK/PD-BASED MODEL PREDICTIVE CONTROL OF BLOOD GLUCOSE 1497

Fig. 3. In silico evaluation of controller across the virtual cohort by control

variability grid analysis (CVGA, 100%tile). The CVGA displays the minimal
(x-axis) to maximal (y-axis) glucose values (range of control) for all (simulated)
measurements for each individual. Left: Variability in control for duration of the
trial (7:30 p.m., Day 1 to 10 p.m., Day 2). Right: Variability in control overnight
(10 p.m., Day 1 to 8 a.m., Day 2). More details on control performance are given Fig. 5. Schematic of the work and information flow of an integrated system
in Tables I and II and Fig. 4. as applied in a clinical environment to provide continuous closed-loop glucose
control. The PBPK/PD model kernel is initialized with patient data (green;
physiological parameters, e.g., weight, height, gender). Blood glucose is mea-
TABLE I sured frequently (blue) the values are stored, and the most recent are delivered
In Silico CONTROL TRIAL STATISTICS (IV GLUCOSE TRIAL) to the controller. The process works on both extended and short timeframes.
The extended timeframe applies to the offline “optimization/model adaptation”
(blue), which is based on the full measurement data history (outer layer). The
Target Overall Daytime Overnight short timeframe applies to online calculation (red) of the optimal insulin dose
(u (t)) based on recent glucose measurements (middle layer). The MPC with
t in target [%] 84 (72 to 92) 79 (67 to 90) 94 (83 to 100) PID offset control is embedded in the online simulation and control workflow.
t below 52 mg/dl [%] 0∗ (0 to 0) 0 (0 to 0) 0 (0 to 0) Based on the tracking error (e (t)), the weighted actual absolute error (P), the
t below 70 mg/dl [%] 0∗ (0 to 0) 0 (0 to 0) 0 (0 to 0) weighted sum of all past errors (I), and the weighted change in error relative
t above 140 mg/dl [%] 26 (19 to 41) 34 (26 to 46) 6 (0 to 17) to that at the previous sampling point (D) are summarized in the calculating
Mean glucose [mg/dl] 128 132 117 the change in target value for the MPC controller (ΔTV) and the correction in
Glucose stdv [mg/dl] 28 32 11 insulin dose, Δu (t) (innermost layer).
Max. glucose range amplitude [mg/dl] 115 (95 to 134) 115 (95 to 134) 43 (32 to 65)

Targets defined in Section II.

*
Values are given as mean values, and the 5%–95% tile in parentheses. For details, see
Table II.
Values for zero are absolute, not rounded.
Fig. 4. Summary of sensor error-dependent performance of control. Each
large circle represents a trial using a virtual cohort (n = 12) to evaluate the
effects of error (expressed as MARD in%) and the delay (up to 30 min) in
SC measurements. The left part (x-axis points 3–17) represents in silico trials
with artificially generated CGM sensor noise, and the right part (x-axis point 5)
represents the in silico trial with simulated IV measurements (no delay). Each
chart shows (as% of total time) the time at target concentration, the time above
140 mg/dl (hyperglycemia), the time below 70 mg/dl (mild hypoglycaemia),
and the time below 50 mg/dl (hypoglycaemia). The colors indicate whether
control performance is good (green), suboptimal (orange), or critical (red).
Specifically, for each sector, the colors reflect the following: time at target con-
centration: green >80%, orange 60%–80%, red <60%; time above 140 mg/dl:
green <30%, orange 30%–80%, red >50%; time below 70 mg/dl: green <1%,
orange 1%–3%, red >3%; time below 50 mg/dl: green = 0% (absolute value,
not rounded), orange >0% but <1%; red >1%. All values marked as orange
are acceptable under controlled conditions.
relative change of the uniform distribution being 30%. Fig. 1
shows the in silico trial for Subject 08.
Especially during the phase immediately following clamping,
omitting the adaptation step leads to a greater likelihood of
model uncertainties. As the offset controller takes a short time
to adjust for prediction errors, the MPC starts (at t = 330 min)
with a high target value (150 mg/dl), which is gradually reduced
toward the desired target level (110 mg/dl).
For the virtual patient used as an example in Fig. 1, the pre-
dicted half-life for insulin was underestimated (see Table II; SC
insulin binding factor Qfac was underestimated resulting in a
faster release of insulin from the SC injection depot). Thus, the
predicted insulin levels fell more rapidly than the actual lev-
els, and, consequently, the predicted glucose levels rose more
rapidly than the measured levels (e.g., at t = 400 min). This
caused the MPC to supplement insulin prematurely. However,
given that the insulin level in the in silico patient was sufficient
and the glucose level was already below target, the offset con-
troller corrected for (reduced) the premature dose calculated by
the MPC, i.e., the next time glucose rose above the target level
(t > 500 min), the offset controller did not reduce the insulin
dose. This reactive control behavior slightly restricts the predic-
tive capabilities of the MPC and causes the glucose trajectories
to oscillate. Especially in the context of high insulin doses (e.g.,
prandial insulin), an underestimate of the half-life of insulin ac-
tion (i.e., overestimation of insulin clearance) can have serious
consequences; in this example, the large insulin dose at break-
fast at time t = 1100 min resulted in postprandial low glucose
1498 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO. 7, JULY 2016

TABLE II
INDIVIDUAL PARAMETERS AND PERFORMANCE INDICATORS FOR THE IV CONTROL RUN

Individual parameters for in-silico subjects (S1–12) and the corresponding identified values used by the MPC (in parentheses)

Parameter Unit S1 S2 S3 S4 S5 S6 S7 S8 S9 S10 S11 S12

SI a [−] 1.3 (1.2) 1.8 (1.7) 2.6 (1.7) 1.1 (0.8) 1.5 (1.2) 1.3 (1.1) 1 (1) 2.2 (1.7) 1.5 (1.7) 1.3 (1.4) 1.5 (1.2) 1.7 (1.4)
SN b [−] 0.4 (0.5) 2 (0.5) 2 (1) 2 (1) 1.7 (1) 1 (1) 1.1 (0.5) 1 (0.5) 1.1 (1) 1.1 (1) 1.1 (1) 1.1 (1)
Qfa c c [IU/μmol] 1000 1000 3000 2000 1000 1000 2000 3000 2000 3000 3000 2000
(500) (500) (2000) (500) (500) (2000) (2000) (500) (2000) (1000) (2000) (500)
k SI C D d [1/min] 2E−6 2E−6 1E−5 1E−5 5E−6 1E−5 2E−6 8E−6 7E−6 5E−6 1E−5 9E−6
(1E−6) (7E−6) (1E−5) (7E−6) (7E−6) (7E−6) (7E−6) (7E−6) (1E−5) (7E−6) (1E−5) (7E−6)
G F R fIr a c e [−] 2 (1) 2 (1) 3 (1) 1 (1) 5 (1) 2 (1) 2 (1) 1 (1) 1 (1) 1 (1) 5 (1) 2 (1)
G F R fNr a c f [−] 15 (10) 5.5 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10) 10 (10)
G en der [−] Male Female Male Male Male Female Male Male Female Female Male Male
Age [years] 64 43 40 60 40 42 38 57 40 22 41 21
W eig ht [kg] 74 62 73 88 79 66 89 74 55 65 75 75
H eig ht [cm] 173 168 176 180 169 165 190 174 165 166 171 180
BM I [cm/m2 ] 24.73 21.97 23.57 27.16 27.66 24.24 24.65 24.44 20.20 23.59 25.65 23.15
Resulting individual mean and range of blood-glucose values for the IV control run
M ean [mg/dl] 123.3 127.3 126.5 123.3 123.9 137.6 123.0 125.3 132.9 124.6 129.2 123.6
M ax. [mg/dl] 200.8 218.3 220.2 189.2 181.9 205.6 193.5 207.8 212.5 207.6 213.8 186.5
M in . [mg/dl] 89.0 70.2 83.7 82.3 84.0 98.4 78.4 71.4 86.5 76.7 91.6 83.1
t in target∗ [%] 84.9 81.5 86.6 90.8 92.4 73.1 89.9 88.2 76.5 84.0 84.0 91.6

a
Insulin Sensitivity.
b
Glucagon Sensitivity.
c
Subcutaneous insulin binding factor.
d
Subcutaneous insulin degradation rate constant.
e
Renal insulin clearance factor.
f
Renal glucagon clearance factor.
*
No hypoglycemia, thus the remaining time was spent > 180 mg/dl.

levels at t = 1250 min as the decline of insulin action/levels
was slower than that predicted by the MPC. However, over-
all the glucose trajectories stayed well within the target range,
even after a glucose disturbance occurred at t = 1560 min (as
elaborated in the next section).
2) Effects of Disturbances: Even with improvements in the
sensor and pump technologies, AGC continues to rely on the
controller being able to cope with both inaccuracies in glucose
sensing and delays in insulin action. These issues are particularly
problematic when a system disturbance, e.g., an unannounced
meal, occurs and triggers a rise in glucose that is substantially
faster than insulin can be absorbed and exert its activity [8].
Another type of disturbance that can trigger such problems is a
change in metabolism, e.g., as a consequence of exercise, stress,
or medical treatment.
For the purpose of evaluating the model’s ability to reject dis-
turbances, an intake of one glass of orange juice (12 g glucose)
was triggered at 4 p.m. on day 2 (t = 1560 min). As shown for
Subject 06 in Fig. 2, the resulting discrepancies between the
model predictions and measurements trigger both a rapid reac-
tion by the offset controller and a slow and steady shift from
the dynamic target value. In spite of an overprediction of the
half-life of insulin, the disturbance is managed well and does
not result in a controller overreaction.
3) Effects of Error/Noise and Overall Performance: The con-
trol algorithm for glucose measurements was tested on measure-
ments with a MARE of 5%. Although the algorithm will first be
evaluated in a clinical setting in which measurement will be IV,
dosing will be SC and the expected MARE will be below 2% (a
higher simulated MARE was chosen for the purpose of making
the evaluation conservative). As our results show (see Figs. 1
and 2), noise at the level chosen for the simulation did not have
a significant adverse effect on the glucose control.
To assess overall performance of the control system through-
out the cohort, we performed control variability grid analysis on
the control results (CVGA, Fig. 3) [39]. This revealed that the
glucose trajectories were well within the normoglycemic range;
episodes of hypoglycemia were absent.
Also, the nighttime control (see Fig. 3, right panel) was com-
pletely within the target range, with the mean blood-glucose
level only slightly above target value. More details on control
performance are given in Tables I and II and Fig. 4.
B. In Silico Evaluation of an Online Controller (SC
Measurement of Glucose)
As a step forward and for the sake of compatibility with cur-
rent state-of-the-art systems, the algorithm for glucose control
in subjects with T1DM was adapted to work with SC mea-
surements of glucose from CGM devices (e.g., Dexcom G4
Platinum, MARE of 10.8 ± 9.9% [38], with glucose readouts
every 5 min). This integrated system has been thoroughly eval-
uated in silico in an extensive robustness analysis that assesses
measurement errors and potential time delays associated with
SC methods of measurement. The ultimate aim is to define ac-
curacy criteria for the required sensor system.
For each of the 12 in silico patients, we tested 15 artificial
error/time-delay sets, producing a total of 180 trial runs. The
error/time-delay sets were assembled based on the assumption
SCHALLER∗ et al.: ROBUST PBPK/PD-BASED MODEL PREDICTIVE CONTROL OF BLOOD GLUCOSE
Fig. 6. General mechanistic principles of a PBPK organ representation (in PK-
Sim) with four subcompartments [intracellular (cell), interstitial (int), plasma
(pl) and blood cells (bc)] and the corresponding flow rates and transports. C:
concentrations, Q: flow rates, P ∗ SA: permeability surface area products, K:
partition coefficient, V ma x , Km : Michaelis–Menten constants, for exam-
ple, transport or metabolization processes (figure taken from [1]. For explicit
representations in the glucose-insulin model please refer to [4]).
Fig. 7. Schematic of the MPC. Solving the optimization problem P at time
k over the prediction horizont N (here, N = 8 sampling points) results in the
(online) feedback control law uk . The collected data before time k resulting
from past control is used for internal model adaptation [calculated offline, here:
growing horizon estimator (GHE)] of the MPC by solving the optimization
problem J with respect to the model parameters p using a growing horizon
(N = k) or a moving horizon (N = constant) estimator (not described here,
see [2]). Once control is initiated, MPC is continuously updated with new
model parameters to improve the feedback control, whereas P is solved at
every sampling point, J is generally solved only once every few sampling
points (here at every fourth).
that sensor error would range from 3% to 17% MARE, and that
the delay would range from 0 to 30 min.
The results of the robustness analysis are depicted in a traffic-
light plot (see Fig. 4). They indicate that an increase in MARE
leads to an overall reduction in glucose levels as the % of time
at target increases (for the zero time-delay cases), but also to an
increase in the prevalence of hypoglycaemic events. In contrast,
increasing the time delay increases the prevalence of hypergly-
caemia due to increased glucose fluctuations.
IV. DISCUSSION
We have developed a novel approach to individualized AGC
by integrating, for the first time, a detailed generic whole-
body PBPK/PD model [4] into a robust MPC algorithm. We
1499
evaluated the effectiveness of this approach in controlling glu-
cose by carrying out a post hoc in silico study. The algorithm
was tested against model uncertainty using suboptimal model
fits, with the scenarios tested incorporating glucose-sensor noise
and unprogrammed carbohydrate disturbances. As input, the al-
gorithm requires only the individual’s physiologic properties
(height, weight, gender, and age) and the quantities of carbohy-
drates consumed. We found that the combination of a predictive
system (MPC) with a reactive system (FMPD) significantly in-
creases the controller’s robustness with respect to uncertainty.
All control insulin inputs are calculated and no additional pre-
meal insulin bolus is required. Overall, the controller performs
well. Although most systems currently available have been de-
veloped for the SC measurement of glucose, the controller de-
veloped here uses a novel PBPK/PD model kernel, and because
its initial clinical testing will be done using measurements of
plasma glucose (for safety reasons), our in silico evaluation
included this procedure.
Many algorithms have been developed for AGC [40]–[42].
Among these, MPC is currently favored for a number of reasons:
it is a predictive approach that can manage time delays inherent
to the system (SC glucose monitoring and SC insulin infusion);
it is model-based, which allows for straightforward personal-
ization using patient-specific parameterization [43]; and it is
optimization-based, making it possible to integrate performance
specifications by constraining states (i.e., penalizing for hypo-
glycaemia) and inputs (insulin or glucagon infusion).
The common approach of AGC using MPC is to adapt, in
addition to global model adaptation (time-invariant patient-
specific parameterization), a single input–output sensitive pa-
rameter per sampling time. This accounts for process variability
over time (intraindividual or intraday variability), and results in
a discrete time-dependent profile for this parameter. Usually, a
parameter representing insulin sensitivity in the model is cho-
sen for this time-dependent adaptation [22], [44]. Feedforward
calculation of the control input is then also based on sensitivity
identified using past measurement data.
In this study, only a global time-invariant patient-specific
adaptation of the model was conducted (model individualiza-
tion using all available measurement data) to improve prediction
of the individual’s core dynamics. Unlike other systems [22],
[44], the model adaptation used here does not accommodate for
short-term changes in insulin sensitivity, as this is thought to
be at least partly captured by the mechanistic structure of the
internal model itself, e.g., through insulin receptor and glucagon
dynamics [4]. A different approach was chosen for managing
the remaining intraindividual variability because establishing a
time-dependent insulin sensitivity profile within the PBPK/PD
framework is too time consuming. The intraday variability (un-
certainties and disturbances, i.e., the prediction/measurement
mismatch [45] also on a shorter timescale) is, thus, handled by
the dynamic shift in the target value and the dose-correction
components of the (FMPD) offset controller. In contrast to
other set-point optimization approaches [46], the offset con-
troller is used only to improve the robustness of the approach;
it is not used to anticipate behavioral patterns of the controlled
1500 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO. 7, JULY 2016

TABLE III and an accompanying loss of system flexibility, and, thus, a re-
PARAMETERS FOR THE CONTROL ALGORITHM
duced ability to accommodate for extreme short-term changes in
patient behavior.
Parameter Value Dimension Description Source
MPC
V. CONCLUSION
UT 140 [mg/dl] Upper glucose target range limit GCP
LT 70 [mg/dl] Lower glucose target range limit GCP Over the years, MPC has established itself as the benchmark
WTV 100 [−] Weight for target value cost function fit in AGC systems research.
c 2 [−] Ordinate shift for value cost function fit
WN G S 1/2000 [−] Weight for negative slope penalty fit
To address relevant issues in blood-glucose control such as
kd 1/100 [−] Gain for negative slope penalty fit system lag time and variability, as well as sensor inaccuracy,
W E IO B 3000 [−] Weight of insulin-on-board constraint fit we have developed a robust nonlinear MPC using a PBPK/PD
Offset Controller (FMPD) model that captures absorption, distribution, and metabolization
K pΔ T V 0.2 [−] Controller gain for P-controller fit
K iΔ T V 0.02 [−] Controller gain for I-controller fit of glucose, insulin, and glucagon, as well as interactions among
W pΔ T V 0.02 [−] Forgetting factor for P-controller fit them.
K pΔ u 4e-8 [U/(mg/dl)] Controller gain for P-controller fit To ensure robustness of the developed algorithm, a thorough
K iΔ u 1e-9 [U/(mg/dl)] Controller gain for I-controller fit
K dΔ u 5e-7 [U/(mg/dl)] Controller gain for D-controller fit robustness evaluation was conducted. This analysis revealed
W pΔ u 0.02 [−] Forgetting factor for P-controller fit that our approach could cope with sensor noise of a MARD of
W dΔ u 0.1 [−] Forgetting factor for D-controller fit 10%–14% which is sufficient to cover the measurement errors
W E IO B 30 [−] Weight of insulin-on-board constraint fit
kp , d 3 [−] Constant for gain scheduling fit made by current state-of-the-art CGMs.
The new approach, which uses a generic PBPK platform,
also allows seamless integration, i.e., extension, of the AGC
with other PBPK diabetes modeling and simulation work. It is
individual. Also, gain scheduling is applied for safety reasons possible to integrate established PBPK models for treatment of
(“pump shutoff”) but not to adapt to patient characteristics [14]. diabetes with different types of insulin, treatments not involving
Although controller performance was good, our analysis in- insulin, or treatment of comorbidities [4].
dicates opportunities for improvement in future versions. First, In summary, the current study describes and evaluates, both
model uncertainties in predicting insulin dynamics (due to er- in silico and through retrospective analysis, a blood-glucose
rors in the estimated half-life of insulin) result in inverse os- control system that combines a highly predictive whole-body
cillation of patient plasma glucose levels and rates of insulin PBPK/PD model [4] with an MPC framework and a dose-
infusion. This phenomenon can have serious consequences in correction module capable of reacting to unpredictable patient
the case of high (e.g., prandial) insulin doses but can be at- behavior and handling uncertainty in model predictions and
tenuated by model adaptation. Second, state-of-the-art systems measurements. This approach holds great promise for AGC, and
work through the SC–SC route, which is explicitly mapped by its effectiveness will be further evaluated in a clinical setting.
the current model kernel (interstitial fluid kinetics of glucose in
skin, muscle, and fat, and insulin absorption in SC tissue [4])
APPENDIX
but subject to physiological (plasma to interstitial) and technical
(CGM signal processing) time delays. Although interstitial fluid Here, we describe the components and constraints relevant to
kinetics of the model and the simulated CGM sensor noise were the interactions among components of the integrated modular
evaluated in silico here, it remains to be determined (within approach as depicted in Fig. 5.
a real-clinical trial) whether their modeling is sufficiently ac- A. PBPK Model Basis and Simulation of Blood-Glucose
curate for adequate description of SCGM by CGM devices or Concentrations: The basis for the model is the combination of
if associated interoccasion variability in the measurements can formalisms for drug distribution with the spatial structure of
critically affect controller performance. the physiology-based compartmentalization [1]. Here, a brief
The MPC-based AGC system tested here has been devel- description of whole-body PBPK modeling is given. A more
oped for use in a clinical environment. As such, the next step in-depth description is provided in a published description of a
would be to go beyond evaluation with respect to model un- workshop [47]; this provides insight into the essential structural
certainty and carbohydrate disturbances, and to establish an elements and theoretical concepts that underlie a PBPK model,
understanding of how well the system copes with illness, med- with additional in-depth technical detail in [48]–[50] and detail
ication, stress (e.g., in an intensive-care setting), and physical on the database in [51].
exercise. Although the unprogrammed carbohydrate challenge In short, within a PBPK model, compound concentrations in
experiment indicates that the controller can manage significant subcompartments (vascular, interstitial, and cellular space) of
disturbances, it remains to be determined how predictive (i.e., all major organs are calculated. Compounds distribute via blood
elaborate) such a system should be if it does not explicitly ac- flows and diffusion processes or active transport processes me-
count for all external or internal disturbances to glucose dynam- diated by transport protein as shown in Fig. 6. This approach is
ics. Although the predictive control approach is essential to cope also used to calculate the IV (muscle/fat vascular space) and SC
with time delays in SC administration of insulin, the tradeoff for (fat interstitial space) glucose concentrations to be used as ob-
high-level prediction is the need for high computational power served variables [simulated blood-glucose prediction, x (t)) for
SCHALLER∗ et al.: ROBUST PBPK/PD-BASED MODEL PREDICTIVE CONTROL OF BLOOD GLUCOSE
blood-glucose control]. The PBPK/PD model used for these cal-
culations is based on coupling PBPK models of glucose, insulin,
and glucagon via their interactions, i.e., pharmacodynamics [4].
The PD functions of the model are directly adapted from
Sorensen [52] with the modifications (parameterization) and
extensions (insulin receptor model and incretin effect model)
documented in the supplementary information of [4] (the sup-
plementary information also includes a model file; the soft-
ware (PKSim/MoBi) and MATLAB are both required to run
the provided model. The software is available free of charge
(after registration) for academic use (http://www.systems-
biology.com/uc/download.html).
PBPK models are extensively used in various applications,
including drug–drug interaction studies and pediatric trial sim-
ulations, as well as in regulatory submissions (US Food and
Drug Administration) during the development of pharmaceuti-
cals [53]–[57].
B. Effect of Insulin on Board (EIOB): We designed a
penalty function to account for the EIOB. Its functions are
parameterized such that only those insulin doses that lead to
oversaturation of the pharmacodynamic effect at the target tis-
sue are penalized. The EIOB functions for hepatic (EIOBliv )
and peripheral/muscular (EIOBmus ) insulin action are calcu-
lated based on the individual’s insulin sensitivity (SI ) and the
amount of phosphorylated insulin receptor, as follows:
WEIOB (SI IReff )8
EIOB (IReff ) = (7)
8 + (S IR )8
Km I eff
with the relative effect of phosphorylated insulin receptors in the
respective tissue represented by IReff = IRp /IRp0 , where the
number of phosphorylated insulin receptors is IRp , the number
of basal phosphorylated insulin receptors IRp0 , the threshold
value Km , and the weight of the constraint WEIOB . When the
PBPK/PD model is individualized, the pharmacodynamic func-
tions are automatically adapted via the insulin sensitivity factor
(parameter SI ), and, thus, the EIOB for each subject is also
individualized.
Km is calculated based on the patient’s basal state at the
beginning of the clamp phase, and EIOB is solved for Km
with EIOB (IReff = Km ) = 1. The constraint for EIOB was
used for both the FMPD controller and the MPC algorithm.
The details of how the EIOB was applied within the respective
control system are provided below.
C. MPC Cost Function: The performance of the MPC
algorithm strongly depends on the design of the cost function
V (x, k, u) (see Fig. 7), and that of the stage cost l (xi ). A
general approach would be to use a sum-of-squares function to
penalize the control errorl (xi ) = f (DT V, xi ) (dynamic target
value versus predicted glucose). However, as hypoglycemia is
more critical than hyperglycemia, an asymmetrical cost function
was chosen. Specifically, we chose two overlapping exponential
functions, with the one penalizing low glucose levels (lower
threshold value function (LTHV)] defined as
 mg 
LTHVi = e1/8(L T −x i ) , with LT = DT V − 40 (8)
dl
1501
the one penalizing high glucose levels (upper threshold value
function UTHV)] defined as:
 mg 
UTHVi = e1/70(x i −U T ) , with U T = DT V − 10 (9)
dl
and the stage cost being
l (xi ) = WTV (LTHVi + UTHVi − c) (10)
with weight WTV and the correction constant c chosen to set
l (xi = DT V ) = 0.
1) Effect of Insulin on Board (MPC): In the case of insulin
oversaturation, the MPC cost function is penalized, with the
EIOB value (7) added to the cost function.
2) Negative Slope: A negative slope of the blood-glucose
trajectory at glucose concentrations around or below the target
value is undesirable, as this indicates that glucose levels continue
to fall. Thus, where the slope was negative, a penalty was added
to the cost function V (x, k, u). This penalty was defined as
k
+N
N GS = WN G S −ẽi · exp (−kd (ẽi − ẽi−1 ))
i=k
with ẽi = (xi − DT V ) , if (ẽi − ẽi−1 ) < 0 (11)
with the penalty weight WN G S and the gain constant kd . This
results in the objective function
k+N 
V (x, k, u) = WTV (LTHVi + UTHVi − c)
i=k

−WN G S (ẽi · exp (−kd (ẽi − ẽi−1 )))
+EIOBmus
i + EIOBliv
i + uk . (12)
D. FMPD Constraints:
1) Effect of Insulin on Board (the FMPD Controller): Con-
trolling blood glucose via the SC route introduces significant
delays between that time at which the controller input is applied
and the time at which its effects are initiated. These delays pose
a major challenge in glucose control, as they generally cause
the system to both overshoot with respect to insulin levels, and,
more importantly, undershoot with respect to glucose levels. If
not managed properly, these effects can result in severe episodes
of hypoglycemia. Feedback systems with delays are especially
prone to overshoot following severe disturbances. In the case
of glucose control, this can be after a meal is consumed or a
physical activity is undertaken.
The FMPD controller used to circumvent these problems is
combined with the EIOB constraint by weighing the dose cor-
rection Δuk with the sum of the weighted EIOB constraints,
resulting in the effective value for the dose correction Δuk , as
shown in (13) at the top of the next page.
1502
k  
Kp j =0 e−W p (k −j ) êj + Ki kj=0 êj + Kd kj=0 e−W d (k −j ) (êj − êj −1 )
Δuk =
1 + EIOBliv + EIOBmus
2) Gain Scheduling: In general, a standard PD or PID con-
troller is symmetric, i.e., both positive and negative deviations
from the target value are treated equally by counteracting con-
trol actions. Here, however, control is one-sided, because insulin
is infused without any counteracting control input. Below-target
episodes of glucose levels are commonly managed by fully sus-
pending activity of the insulin pump whenever blood-glucose
levels dip below the target value. However, our experience with
the dataset at hand showed that extremely low insulin levels
(which can be reached when the pump is fully suspended) trig-
ger excessive hepatic glucose output and the release of large
amounts of glucose. Thus, rather than completely suspend-
ing pump activity, we reduced the input gain for insulin infu-
sions below target value to avoid depleting the insulin pool. We
calculated the adjusted controller gains as
K̃p,d = Kp,d (1 + 3ē (t)) , if ē (t) < 0, with ē (t)
= (y (t) − TV) /TV. (14)
All control inputs calculated as negative were set to zero.
E. CGM In Silico Sensor Noise: Artificial error signal was
calculated using the method described by Fachinetti et al. [58].
The SC measurement (SCGM) signal is calculated as
SCGM (t) = (1 + s (t)) IG (t) + v (t) (15)
with v (t) representing a Gaussian noise signal (zero mean, max.
rel. error 35%), IG (t) the actual interstitial (i.e., SC) glucose
levels, and s (t) the error drift factor generated from integration
of a Gaussian noise signal, as
s (t + 1) = 3s (t) − 3s (t − 1) + s (t − 2) + w (t) (16)
with w(t) as the Gaussian noise (zero mean and max 1% random
drift per time step of 15 min) that results in a maximal relative
drift of max(s) = 80% within a 24-h time interval.
The artificial SCGM (SCGM(t)) was, thus, generated by su-
perimposing the single artificial sensor noise signal profile on the
raw glucose trajectories from the SC compartment (interstitial
skin) of the simulated individual.
ACKNOWLEDGMENT
The authors would like to thank S. Willmann and
M. Krauss for fruitful discussion and T. Gaub, J. Solodenko,
and K. Coboeken for the strong technical support as platform
developers. S. Schaller designed and performed the research,
analyzed the data, and developed the control algorithm, the
model kernel, and modeling tools, and J. Lippert, A. Schuppert,
and T. Eissing designed research and developed the modeling
tools. L. Schaupp and T. R. Pieber contributed the clinical data.
All authors helped in preparing this paper.
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO. 7, JULY 2016
(13)
REFERENCES
[1] S. Willmann et al., “PK-Sim R
: A physiologically based pharmacokinetic
‘whole-body’ model,” Biosilico, vol. 1, pp. 121–124, 2003.
[2] J. B. Rawlings, and D. Q. Mayne, Model Predictive Control Theory and
Design. Madison, WI, USA: Nob Hill, 2009.
[3] R. Hovorka, “Closed-loop insulin delivery: From bench to clini-
cal practice,” Nature Rev. Endocrinol., vol. 7, no. 7, pp. 385–395,
2011.
[4] S. Schaller et al., “A generic integrated physiologically-based whole-
body model of the glucose-insulin-glucagon regulatory system,” CPT,
Pharmacometrics Syst Pharmacol., vol. 2, no. 8, art. no. e65, 2013.
doi:10.1038/psp.2013.40
[5] International-Diabetes-Federation, IDF Diabetes Atlas, Brussels,
Belgium, 2013.
[6] B. Kovatchev, “Closed loop control for type 1 diabetes,” BMJ, vol. 342,
art. no. d1911, 2011. doi: 10.1136/bmj.d1911
[7] B. W. Bequette, “A critical assessment of algorithms and challenges in
the development of a closed-loop artificial pancreas,” Diabetes Technol.
Ther., vol. 7, no. 1, pp. 28–47, Feb. 2005.
[8] C. Cobelli et al., “Artificial pancreas: Past, present, future,” Diabetes,
vol. 60, no. 11, pp. 2672–2682, Nov. 1, 2011.
[9] E. Dassau et al., “Closing the loop,” Int. J. Clin. Pract. Suppl., vol. 65,
no. 166, pp. 20–25, Feb. 2010.
[10] R. Hovorka et al., “Overnight closed loop insulin delivery (artificial
pancreas) in adults with type 1 diabetes: Crossover randomised controlled
studies,” BMJ, vol. 342, art. no. d1855, Apr. 2011. doi: 10.1136/bmj.d1855
[11] G. M. Steil et al., “Closed-loop insulin delivery-the path to physiological
glucose control,” Adv. Drug Del. Rev., vol. 56, no. 2, pp. 125–144, Feb.
10, 2004.
[12] B. Gopakumaran et al., “A novel insulin delivery algorithm in rats with
type 1 diabetes: The fading memory proportional-derivative method,” Ar-
tif. Organs, vol. 29, no. 8, pp. 599–607, Aug. 2005.
[13] J. R. Castle et al., “Novel use of glucagon in a closed-loop system
for prevention of hypoglycemia in type 1 diabetes,” Diabetes Care,
vol. 33, no. 6, pp. 1282–1287, Jun. 2010.
[14] P. G. Jacobs et al., “Automated control of an adaptive bihormonal,
dual-sensor artificial pancreas and evaluation during inpatient stud-
ies,” IEEE Trans. Biomed. Eng., vol. 61, no. 10, pp. 2569–2581,
Oct. 2014.
[15] P. G. Jacobs et al., “Development of a fully automated closed loop ar-
tificial pancreas control system with dual pump delivery of insulin and
glucagon,” in Proc. IEEE Annu. Int. Conf. Eng. Med. Biol. Soc., 2011,
pp. 397–400.
[16] A. Dauber et al., “Closed-loop insulin therapy improves glycemic control
in children aged <7 years: A randomized controlled trial,” Diabetes Care,
vol. 36, no. 2, pp. 222–227, Feb. 1, 2013.
[17] M. J. O’Grady et al., “The use of an automated, portable glucose control
system for overnight glucose control in adolescents and young adults with
type 1 diabetes,” Diabetes Care, vol. 35, no. 11, pp. 2182–2187, Nov. 1,
2012.
[18] E. Atlas et al., “MD-logic artificial pancreas system: A pilot study in adults
with type 1 diabetes,” Diabetes Care, vol. 33, no. 5, pp. 1072–1076, May
2010.
[19] S. Miller et al., “Automatic learning algorithm for the MD-logic ar-
tificial pancreas system,” Diabetes Technol. Ther., vol. 13, no. 10,
pp. 983–990, Oct. 2011.
[20] J. El Youssef et al., “A review of closed-loop algorithms for glycemic
control in the treatment of type 1 diabetes,” Algorithms, vol. 2, no. 1,
pp. 518–532, 2009.
[21] R. S. Parker et al., “A model-based algorithm for blood glucose control
in type I diabetic patients,” IEEE Trans. Biomed. Eng., vol. 46, no. 2,
pp. 148–157, Feb. 1999.
[22] R. Hovorka et al., “Nonlinear model predictive control of glucose con-
centration in subjects with type 1 diabetes,” Physiol. Meas., vol. 25,
no. 4, pp. 905–920, Aug. 2004.
[23] L. Magni et al., “Run-to-run tuning of model predictive control for type
1 diabetes subjects: In silico trial,” J. Diabetes Sci. Technol., vol. 3, no. 5,
pp. 1091–1098, 2009.
SCHALLER∗ et al.: ROBUST PBPK/PD-BASED MODEL PREDICTIVE CONTROL OF BLOOD GLUCOSE
[24] S. J. Russell et al., “Blood glucose control in type 1 diabetes with a
bihormonal bionic endocrine pancreas,” Diabetes Care, vol. 35, no. 11,
pp. 2148–2155, Nov. 2012.
[25] P. Soru et al., “MPC based artificial pancreas: Strategies for individ-
ualization and meal compensation,” Annu. Rev. Control, vol. 36, no. 1,
pp. 118–128, 2012.
[26] L. Leelarathna et al., “Day and night home closed-loop insulin delivery
in adults with type 1 diabetes: Three-center randomized crossover study,”
Diabetes Care, vol. 37, no. 7, pp. 1931–1937, Jul. 2014.
[27] S. Del Favero et al., “First use of model predictive control in out-
patient wearable artificial pancreas,” Diabetes Care, vol. 37, no. 5,
pp. 1212–1215, May 2014.
[28] C. Dalla Man et al., “Meal simulation model of the glucose-insulin
system,” IEEE Trans. Biomed. Eng., vol. 54, no. 10, pp. 1740–1749, Oct.
2007.
[29] B. P. Kovatchev et al., “In silico preclinical trials: A proof of concept
in closed-loop control of type 1 diabetes,” J. Diabetes Sci. Technol.,
vol. 3, no. 1, pp. 44–55, 2009.
[30] R. Hovorka et al., “A simulation model of glucose regulation in the
critically ill,” Physiol. Meas., vol. 29, no. 8, pp. 959–978, Aug. 2008.
[31] T. Eissing et al., “A computational systems biology software platform for
multiscale modeling and simulation: Integrating whole-body physiology,
disease biology, and molecular reaction networks,” Front. Physiol., vol. 2,
no. 4, pp. 1–10, 2011. doi:10.3389/fphys.2011.00004
[32] A. Strougo et al., “First dose in children: Physiological insights into
pharmacokinetic scaling approaches and their implications in paedi-
atric drug development,” J. Pharmacokinet. Pharmacodyn., vol. 39,
pp. 195–203, Feb. 5, 2012.
[33] R. Hovorka et al., “Closing the loop: The adicol experience,” Diabetes
Technol. Ther., vol. 6, no. 3, pp. 307–318, Jun. 2004.
[34] D. Q. Mayne et al., “Constrained model predictive control: Stability and
optimality,” Automatica, vol. 36, no. 6, pp. 789–814, 2000.
[35] R. C. Dorf, and R. H. Bishop, Modern Control Systems, 12th ed. Engle-
wood Cliffs, NJ, USA: Prentice-Hall, 2011.
[36] G. F. Franklin et al., Feedback Control of Dynamic Systems, 4th ed.
Englewood Cliffs, NJ, USA: Prentice-Hall, 2002.
[37] Mueller. Dr. Mueller Geraetebau. (2015). [Online]. Available: http://www.
dr-mueller-geraetebau.de/
[38] E. R. Damiano et al., “A comparative effectiveness analysis of three
continuous glucose monitors: The navigator, G4 Platinum, and enlite,” J.
Diabetes Sci. Technol., vol. 8, pp. 699–708, Apr. 21, 2014.
[39] L. Magni et al., “Evaluating the efficacy of closed-loop glucose regulation
via control-variability grid analysis,” J. Diabetes Sci. Technol., vol. 2, no.
4, pp. 630–635, Jul. 2008.
[40] F. J. Doyle et al., “Closed-loop artificial pancreas systems: Engineering
the algorithms,” Diabetes Care, vol. 37, no. 5, pp. 1191–1197, May 1,
2014.
[41] P. A. Bakhtiani et al., “A review of artificial pancreas technologies
with an emphasis on bi-hormonal therapy,” Diabetes Obesity Metab.,
vol. 15, no. 12, pp. 1065–1070, Dec. 2013.
[42] R. Hovorka et al., “Assessing performance of closed-loop insulin delivery
systems by continuous glucose monitoring: Drawbacks and way forward,”
Diabetes Technol. Ther., vol. 15, no. 1, pp. 4–12, Jan. 2013.
[43] B. P. Kovatchev, “Diabetes technology: Markers, monitoring, assess-
ment, and control of blood glucose fluctuations in diabetes,” Scien-
tifica, Cairo, vol. 2012, art. no. 283821(14 pages), pp. 1–14, 2012.
doi:10.6064/2012/283821
[44] R. Hovorka et al., “Blood glucose control by a model predictive control
algorithm with variable sampling rate versus a routine glucose manage-
ment protocol in cardiac surgery patients: A randomized controlled trial,”
J. Clin. Endocrinol. Metab., vol. 92, no. 8, pp. 2960–2964, Aug. 2007.
[45] B. W. Bequette, “Algorithms for a closed-loop artificial pancreas: The
case for model predictive control,” J. Diabetes Sci. Technol., vol. 7, no. 6,
pp. 1632–1643, Nov. 2013.
[46] Y. Wang et al., “Model predictive control with learning-type set-point:
Application to artificial pancreatic β-cell,” AIChE J., vol. 56, no. 6,
pp. 1510–1518, 2010.
[47] H. M. Jones and K. Rowland-Yeo, “Basic concepts in physiologically
based pharmacokinetic modeling in drug discovery and development,”
CPT, Pharmacometrics Syst. Pharmacol., vol. 2, no. 8, art. no. e63,
pp. 1–12, 2013. doi:10.1038/psp.2013.41
[48] T. Rodgers et al., “Physiologically based pharmacokinetic modeling 1:
Predicting the tissue distribution of moderate-to-strong bases,” J. Phar-
maceutical Sci., vol. 94, no. 6, pp. 1259–1276, Jun. 2005.
1503
[49] T. Rodgers, and M. Rowland, “Physiologically based pharmacokinetic
modelling 2: Predicting the tissue distribution of acids, very weak
bases, neutrals and zwitterions,” J. Pharmaceutical Sci., vol. 95, no. 6,
pp. 1238–1257, Jun. 2006.
[50] W. Schmitt, “General approach for the calculation of tissue to plasma
partition coefficients,” Toxicol. In Vitro, vol. 22, no. 2, pp. 457–467, Mar.
2008.
[51] S. Willmann et al., “Development of a physiology-based whole-body
population model for assessing the influence of individual variability
on the pharmacokinetics of drugs,” J. Pharmacokinet. Pharmacodyn.,
vol. 34, no. 3, pp. 401–431, Jun. 2007.
[52] J. T. Sorensen, “A physiologic model of glucose metabolism in man and
its use to design and assess improved insulin therapies for diabetes,” Ph.D.
dissertation, Dept. Chem. Eng., Massachusetts Inst. Technol., Cambridge,
MA, USA, 1985.
[53] R. Leong et al., “Regulatory experience with physiologically based phar-
macokinetic modeling for pediatric drug trials,” Clin. Pharmacol. Thera-
peutics, vol. 91, no. 5, pp. 926–931, 2012.
[54] P. Zhao et al., “Applications of physiologically based pharmacokinetic
(PBPK) modeling and simulation during regulatory review,” Clin. Phar-
macol. Therapeutics, vol. 89, no. 2, pp. 259–267, 2011.
[55] A. R. Maharaj and A. N. Edginton, “Physiologically based pharmacoki-
netic modeling and simulation in pediatric drug development,” CPT, Phar-
macometrics Syst. Pharmacol., vol. 3, no. 11, pp. 1–13, 2014.
[56] A. R. Maharaj et al., “A workflow example of PBPK modeling to support
pediatric research and development: Case study with lorazepam,” AAPS
J., vol. 15, no. 2, pp. 455–464, Apr. 1, 2013.
[57] H. M. Jones et al., “Physiologically based pharmacokinetic modeling in
drug discovery and development: A pharmaceutical industry perspective,”
Clin. Pharmacol. Ther., vol. 97, no. 3, pp. 247–262, Mar. 2015.
[58] A. Facchinetti et al., “Reconstruction of glucose in plasma from interstitial
fluid continuous glucose monitoring data: Role of sensor calibration,”
J. Diabetes Sci. Technol., vol. 1, no. 5, pp. 617–623, Sep. 2007.
Stephan Schaller was born in Stuttgart, Germany, in
1984. He received the Diploma degree in control sys-
tems engineering from the University of Stuttgart,
Stuttgart, in 2009, and the Ph.D. degree in com-
putational engineering from the Aachen Institute
for Advanced Studies in Computational Engineer-
ing Science, RWTH Technical University of Aachen,
Aachen, Germany, in 2014.
Since 2013, he has been a Biological Modeling
Expert at Bayer Technology Services, GmbH, Lev-
erkusen, Germany. Since 2015, he has also been a
Senior Systems Pharmacology Scientist at Sanofi Deutschland GmbH, Frank-
furt, Germany. Besides carrying out PBPK/PD and systems biology modeling
and consulting in this area, he is developing an algorithm for automated blood-
glucose control using physiologically based pharmacokinetic/dynamic model
kernels within a model predictive control framework.
Mr. Schaller received the “Hans Günter Schäfer-PK/PD-Science-Award” in
2014.
Jörg Lippert, photograph and biography not available at the time of publication.
Lukas Schaupp received the Diploma and Ph.D. de-
grees in electrical and biomedical engineering from
the Graz University of Technology, Graz, Austria, in
1992 and 1998, respectively.
In 1995, he attended the Postgraduate Internship
Program with the Whiting School of Engineering,
Johns Hopkins University, Baltimore, USA (Applied
Physics Laboratory). From 1998–2001, he was a Re-
search Fellow with Karl Franzens University, Graz.
From 2001 to 2009, he was with the Joanneum Re-
search Institute of Medical Technologies and Health
Management, Austria. Since 2001, he has been a Senior Researcher at the
Medical University of Graz, Graz. His main research interests include medical
technologies and devices, with particular focus in diabetes research.
1504
Thomas R. Pieber received the M.D. degree from
the Karl-Franzens-University School of Medicine,
Graz, Austria, in 1987.
He was trained in intensive care medicine, en-
docrinology, and metabolism at the Karl-Franzens-
University, Graz, at the Heinrich-Heine-University,
Düsseldorf, Germany, and at the University of Texas,
Dallas, USA. From 2005 to 2008, he was the Med-
ical Director with the University Hospital Graz,
and he is currently a Head at the Department of
Internal Medicine, Division of Endocrinology and
Metabolism, Medical University of Graz, Graz. Since 2001, he has been a Direc-
tor at the HEALTH—Institute for Biomedicine and Health Sciences, Joanneum
Research, Graz, which carries out research for the development and evaluation
of medical systems, data and health management, and bioanalytics for medical
research. He is an Opinion Leader in the field of diabetes, heading a multidisci-
plinary team of 140 employees, of which approximately half are researchers and
half are healthcare professionals working in the field of diabetes and associated
disorders.
IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 63, NO. 7, JULY 2016
Andreas Schuppert, photograph and biography not available at the time of
publication.
Thomas Eissing studied life sciences and biotech-
nology at the University of Stuttgart, Stuttgart, Ger-
many, and at the University of New South Wales,
Sydney, N.S.W., Australia, and received a diploma in
technical biology from the Univeryity of Stuttgart in
2002. He received his Ph.D. degree from the Institute
of Systems Theory and Automatic Control, Stuttgart
in 2007.
In 2007, he joined Bayer Technology Services,
Leverkusen, Germany, where he is involved in phar-
macokinetic, pharmacodynamic, and systems biol-
ogy modeling and consulting. In 2012, he became the Group Head of Systems
Biology, and in 2014, he became the Group Head of Systems Pharmacology
CV.
Dr. Eissing diploma thesis received an award for the best technical biology
thesis of the year, and his Ph.D. thesis received the MTZ award for medical
systems biology.