PBPK Test Simulation

A Test of the PBPK open source simulation software, using the Igari1983 Diazepam model as a reference. See PBPK of Diazepam for the final Diazepam model.

Disclaimer: This article has not been peer reviewed or published. Provided for informational purposes only.

Contents 1 Introduction 1.1 The Physiological Model 1.2 Mass Balance Equations 2 Results 3 Discussion 4 Appendix 5 References 6 See Also

Introduction

This is an initial test of the PBPK simulator, using data and parameters from Igari1983

The Physiological Model

Below is the Physiological Compartment Model used in the simulation. (from Igari1983, and also see Langdon2007)

Physiological Parameters (Human), from Igari1983

Compartment	Volume (% of Total)	Blood flow rate (% of CO)	Input Compartment	Output Compartment
venousBlood	0.0514	1	-	lungs
arterialBlood	0.0257	1	lungs	-
rest	0.1057	0	-	-
adiposeTissue	0.1743	0.041	arterialBlood	venousBlood
skin	0.1114	0.308	arterialBlood	venousBlood
muscle	0.4286	0.047	arterialBlood	venousBlood
gastrointestinalTract	0.0343	0.19	arterialBlood	liver
kidneys	0.0043	0.196	arterialBlood	venousBlood
liver	0.0214	0.06 (Output: 0.25)	arterialBlood	venousBlood
heart	0.0043	0.038	arterialBlood	venousBlood
brain	0.0214	0.12	arterialBlood	venousBlood
lungs	0.0172	1	venousBlood	arterialBlood
Total	1	4	–	–

Where,

• C0 = cardiac output, 6330 ml/min
• Volume Total = 70000 ml (70kg standard human, assumes 1gm/ml density of tissue/fluids)

Substance Dependent Physiological Data

Compartment	diazepam (ng)
	partitionCoefficient (Ctissue/Cplasma)	Adjusted partitionCoefficient (Ctissue/Cbtotal)	clearance (ml/sec.) [adjusted]	massBalance model
venousBlood	1	1	0 [0]	standard
arterialBlood	1	1	0 [0]	standard
rest	-	-	-	-
adiposeTissue	2.74	2.84138	0 [0]	standard
skin	0.72	0.74664	0 [0]	standard
muscle	0.29	0.30073	0 [0]	standard
gastrointestinalTract	0.4	0.4148	0 [0]	standard
kidneys	0.49	0.50813	0 [0]	standard
liver	1.04	1.07848	0.4784 [0.46]	liverMetabolism
heart	0.47	0.48739	0 [0]	standard
brain	0.22	0.22814	0 [0]	standard
lungs	0.69	0.71553	0 [0]	standard

Notes:

• Adjusted partitionCoefficient = partitionCoefficient * blood2PlasmaRatio
• Adjusted clearance = clearance / partitionCoefficient

Dosing Schedule

Dosage Name	Substance	Compartment	Amount	startTime	Type
initial dose of diazepam	diazepam	venousBlood	7e+006 ng	0	intravenous

Simulation Parameters

Parameter	Value
blood2PlasmaRatio	1.037
totalVolume	70000 ml
volumeUnits	ml
timeUnits	sec.
totalFlow (cardiac output, CO)	105.5 ml/sec.
startTime	0 sec.
stopTime	259200 sec.
dTime	1 sec.
numericalIntegration	eulers or RungeKutta

Mass Balance Equations

The mass balance equation for the Liver compartment:

For a generic tissue compartment:

for the lungs compartment:

for the ArterialBlood compartment:

for the VenousBlood compartment:

Results

Below: Experimental data points from Igari1983, should match Venous blood concentrations…

Discussion

The Simulator matched the data from Igari1983

Appendix

The simulation code:

• Igari1983.txt High level descriptive language
• pbpk2cpp CPP program that converts the High level descriptive language to C
• psim.cpp psim.cpp is the output of pbpk2cpp (ready to be compiled and simulated)

References

• Igari1983 – Prediction of diazepam disposition in the rat and man by a physiologically based …, Igari, et al., J Pharmacokinet Biopharm. 1983 Dec;11(6):577-93.
• Langdon2007 – Linking preclinical and clinical whole-body physiologically based pharmacokinetic…, Langdon, et al., Eur J Clin Pharmacol. 2007 May;63(5):485-98. Epub 2007 Mar 8.

See Also

• PBPK of Diazepam
• Simulating Physics with Computers