IVIVE Extrapolation
Scale hepatocyte intrinsic clearance to a supplied liver size and apply the well-stirred hepatic model; binding, blood/plasma partition and physiological parameters must be externally calibrated.
Description
Scale hepatocyte intrinsic clearance to whole-liver units and apply the well-stirred hepatic model.
In vitro–in vivo extrapolation, or IVIVE, scales an assay measurement using physiological quantities to estimate an in vivo parameter. Hepatocyte intrinsic clearance describes removal capacity before accounting for hepatic blood-flow limitation; hepatic clearance incorporates blood flow and binding through a disposition model.1
This tool scales clearance measured per million cells using hepatocellularity, liver mass per body mass, and body mass. It then applies a well-stirred model with a supplied unbound blood fraction and hepatic blood flow. Both clearance outputs are whole-organ mL/min rather than mL/min/kg.
Input units are essential: intrinsic clearance is µL/min per million cells; hepatocellularity is million cells/g; liverGramsPerKg is g/kg; body mass is kg; and blood flow is mL/min. The extraction output is a fraction of hepatic flow, not a percentage.
When to use IVIVE Extrapolation
Use it to inspect the arithmetic of a hepatocyte-based scaling scenario with externally selected physiological and binding values, or compare parameter sensitivity within the same model.
How to use IVIVE Extrapolation and interpret its calculation
- Enter positive intrinsic clearance, hepatocellularity, liverGramsPerKg, bodyMassKg, and hepaticBloodFlowMlPerMinute in the stated units.
- Enter unboundBloodFraction between 0 and 1 and run the extrapolation.
- Read scaledIntrinsicClearanceMlPerMinute before interpreting hepaticClearanceMlPerMinute and hepaticExtractionFraction. Confirm binding conventions and physiological inputs independently.
CLint = CLcell × hepatocellularity × liver g/kg × body kg / 1000; U = fu,b × CLint; E = U / (Q + U); CLhepatic = Q × E The division by 1000 converts µL/min to mL/min. Q is whole-organ hepatic blood flow.
The tool applies the supplied blood-unbound fraction directly to the scaled intrinsic clearance. It has no separate incubation-unbound fraction input; any required assay correction must be made consistently before entering the intrinsic value.
{
"input": {
"intrinsicClearanceMicrolitersPerMinuteMillionCells": 10,
"hepatocellularityMillionCellsPerGram": 100,
"liverGramsPerKg": 20,
"bodyMassKg": 1,
"unboundBloodFraction": 0.5,
"hepaticBloodFlowMlPerMinute": 60
},
"output": {
"scaledIntrinsicClearanceMlPerMinute": 20,
"hepaticClearanceMlPerMinute": 8.571428571428571,
"hepaticExtractionFraction": 0.14285714285714285
}
}An unbound fraction of zero returns zero hepatic clearance and extraction while preserving positive scaled intrinsic clearance. Intrinsic clearance and flow must be strictly positive. Under the model, extraction is below one and hepatic clearance is below the supplied flow for finite positive inputs.
Limitations and assumptions
Microsomal clearance per mg protein cannot be substituted for clearance per million hepatocytes. The tool does not choose species physiology, convert plasma binding to blood binding, correct incubation binding, or validate assay quality.
It omits transport limitations, extrahepatic clearance, nonlinearity, and uncertainty. Scaling and model assumptions can cause prediction error; no dose recommendation or total-body clearance is produced.
Alternative or Complementary methods
Use experimental measurements and an explicitly justified model when evaluating prediction accuracy. A tissue time-course calculation asks a different question and uses its own clearance convention; do not insert hepatic clearance into it without checking that convention and converting units.
References
-
In vitro-in vivo extrapolation and hepatic clearance dependent underprediction (Bowman and Benet, 2019) — Journal of Pharmaceutical Sciences
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