An introduction to PK-Sim®: the open

source platform for PBPK modeling

Andrea Edginton PhD
School of Pharmacy
University of Waterloo AGENDA (50 min)

aedginto@uwaterloo.ca
Open Systems Pharmacology website
PK-Sim®: small molecule structure and parameterization
Building block philosophy
Making a simulation
Populations and pediatrics
What is MoBi®?
Q&A (10 min or more…)
www.open-systems-pharmacology.org
A (GitHub) place to
• Download PK-Sim®, MoBi® and the GENEDBhuman (MatLab and R-
toolboxes as well)
• Access source code (if you’re savvy like that)
• Find the manuals
• Watch/access tutorials
• View qualification documents
• Ask and answer questions on the community FORUM
• See the bug reports and fixes (ISSUES in PK-Sim or MoBi)
Website
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 Small molecule structure
𝑃𝑃 � 𝑆𝑆𝑆𝑆𝑟𝑟𝑟𝑟𝑟𝑟 B C
Stomach

R 𝑄𝑄𝑟𝑟𝑟𝑟𝑟𝑟
Small Intestine
𝐾𝐾𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖−𝑝𝑝𝑝𝑝𝑝𝑝 plasma 𝑄𝑄𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
Large Intestine
Venous Blood

Pancreas
Arterial Blood
Peripheral venous blood

Spleen 𝑃𝑃 � 𝑆𝑆𝑆𝑆𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
Portal Vein Gallbladder 𝐾𝐾𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐−𝑝𝑝𝑝𝑝𝑝𝑝 interstitial

Liver

Kidney

Adipose
Bone
Brain
Gonads
Heart
Muscle

intracellular
Skin

Lung

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 Small molecule structure
𝑉𝑉𝑟𝑟𝑟𝑟𝑟𝑟 = 𝑉𝑉𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 � 𝑓𝑓𝑣𝑣𝑣𝑣𝑣𝑣 � 𝐻𝐻𝐻𝐻𝐻𝐻

𝐾𝐾𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖−𝑝𝑝𝑝𝑝𝑝𝑝 : partition coefficient 𝑃𝑃 � 𝑆𝑆𝑆𝑆𝑟𝑟𝑟𝑟𝑟𝑟 R B C 𝑄𝑄𝑟𝑟𝑟𝑟𝑟𝑟

defined by binding protein 𝐾𝐾𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖−𝑝𝑝𝑝𝑝𝑝𝑝 Plasma 𝑉𝑉𝑝𝑝𝑝𝑝𝑝𝑝 = 𝑉𝑉𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 � 𝑓𝑓𝑣𝑣𝑣𝑣𝑣𝑣 � 1 − 𝐻𝐻𝐻𝐻𝐻𝐻 𝑄𝑄𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
concentration differential across
endothelium

𝐾𝐾𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐−𝑝𝑝𝑝𝑝𝑝𝑝 : defined by tissue: 𝑃𝑃 � 𝑆𝑆𝑆𝑆𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐

𝐾𝐾𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐−𝑝𝑝𝑝𝑝𝑝𝑝 interstitial 𝑉𝑉𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖 = 𝑉𝑉𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 � 𝑓𝑓𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖
plasma partition coefficient
algorithms (tissue composition
based: lipophilicity, charge, fu)

P: cellular permeability defined

by algorithm using lipophilicity,
molecular weight and charge
(predicts permeability-limited intracellular 𝑉𝑉𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 = 𝑉𝑉𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜𝑜 � 𝑓𝑓𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐
vs. well stirred conditions)

SA: Surface area, quantified 4

 Thelen K, Coboeken K, Willmann S, Burghaus R, Dressman JB, Lippert J.
2011. Evolution of a detailed physiological model to simulate the
gastrointestinal transit and absorption process in humans, part 1: oral

Oral absorption model

solutions. J Pharm Sci. 100(12): 5324-45.

Small intestinal transit time Large intestinal transit time

Gastric emptying time Small Large

(function of food)
Stomach Intestine Intestine
(undissolved)
(1-7) (1-5)
(undissolved) (undissolved)
Dissolution function: particle dissolution
(mechanistic), user defined, Weibull, first
order….etc.
Small Large
Stomach Gastric emptying time Intestine Intestine
(dissolved)
(1-7) (1-5)
(dissolved) (dissolved)

𝑃𝑃𝑖𝑖𝑖𝑖𝑖𝑖 � 𝑆𝑆𝑆𝑆 𝑃𝑃𝑖𝑖𝑖𝑖𝑖𝑖 � 𝑆𝑆𝑆𝑆

mucosa mucosa mucosa Pancreas
Enzymes, transporters
Spleen
Portal Vein
𝑃𝑃𝑖𝑖𝑖𝑖𝑖𝑖 = intestinal permeability,
Liver Systemic circulation estimated using molecular size and
lipophilicity
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Inhalation & dermal absorption
• Not included but can apply in lung or skin via user defined application
• There are numerous mechanistic models in the literature, they could
be incorporated with MoBi
• Create a model in MoBi and generate a plug-in (the future of MoBi
modeling – see Forum Issue #52)
• Plug-ins could be reused with any underlying PK-Sim model

Building Block Philosophy

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Pediatrics in PK-Sim®
• Basic pediatric (term +) parameters:
Edginton AN et al. 2006. Development and evaluation of a generic physiologically based
pharmacokinetic model for children. Clin Pharmacokinet. 45(10):1013-34.
• Preterm (IV only)
Claassen K et al. 2015. Development of a physiologically-based pharmacokinetic model
for preterm neonates: evaluation with in vivo data. Curr Pharm Des. 21(39):5688-98
• Clearance scaling:
Edginton AN et al. 2006. A mechanistic approach for the scaling of clearance in children.
Clin Pharmacokinet. 45(7):683-704
• Updated maturation functions for enzymes and binding protein concentrations in
documentation on GitHub
• Pregnancy
Dallmann A et al. 2017. Gestation-specific changes in the anatomy and physiology of
healthy pregnant women: an extended repository of model parameters for physiologically
based pharmacokinetic modeling in pregnancy. Clin Pharmacokinet. in press.
MoBi 7