Body Size Metrics Used in PBPK Parameterization

Why PBPK Parameterization Needs More Than One Size Metric

A PBPK model describes a particular organism, so its physiological inputs need to correspond to that organism’s characteristics. Body size is one such characteristic, but it is not a single interchangeable number. Total body mass, height, body surface area, and lean body mass describe different aspects of size. The choice matters when a value is reported relative to body size, used in a dose convention, or selected from a reference source.

The earlier material on Reference Physiological Profiles and Covariate Definitions establishes the role of reference characteristics in describing a model organism. This tutorial focuses on four body-size descriptors and the basis on which physiological quantities may be indexed to them. It does not imply that every quantity should be scaled by one of these descriptors: the measurement basis and intended use must guide the choice.

Four Descriptors and Their Bases

Body mass is the organism’s total mass, ordinarily recorded in kilograms (kg). It is straightforward to measure and commonly appears in clinical dose conventions and in physiological data reported per kilogram. However, equal body mass does not imply equal height, body composition, or organ size. Mass is therefore a useful descriptor, not a complete summary of physiology.

Height is a linear measurement, usually recorded in centimetres (cm) or metres (m). It is not usually used alone as a denominator for a whole-body physiological rate, but it contributes to calculated measures such as body surface area and body mass index. A height measurement should be recorded with its units; centimetres and metres cannot be substituted without conversion.

Body surface area (BSA) is an estimated area, conventionally expressed in square metres (m²). It is calculated from body mass and height using an empirical equation. One widely used option is the Mosteller equation:

The equation gives an estimate, not a direct measurement of the body’s complete external surface. Other BSA equations exist, so a source or analysis should identify which equation was used when the distinction could matter.

Lean body mass (LBM) is an estimate of body mass excluding most adipose tissue. It is not directly measured by simply subtracting a known amount of fat in routine data; estimates depend on the method and its assumptions. One commonly used pair of adult equations is the Janmahasatian equation. With body mass \(W\) in kg and body mass index \(BMI\) in kg/m²:

These are prediction equations, not definitions that make LBM an exact known value. Their applicability depends on the population and the sex category for which the equation is being used. A calculated LBM should be labelled as an estimate and should not be presented with more precision than the inputs and model support.

Calculating and Comparing Metrics

BMI is useful here both as a familiar descriptor and as an input to the LBM equations. Its formula also shows why units matter: body mass in kg divided by height squared in m² produces kg/m². Using height in centimetres without conversion would produce a result smaller by a factor of 10,000.

Height and mass can contribute differently to calculated descriptors. For example, a taller person and a shorter person can have similar BMI while having different BSA. Consequently, substituting one descriptor for another can change an indexed value even when both are intended to represent “size.”

Indexing a Quantity: What the Denominator Means

Let \(Q\) be a physiological quantity measured in absolute units, such as a rate in L/h. If the reference is body mass \(W\), its mass-indexed value is \(Q/W\), with units L/h/kg. If the reference is BSA, the corresponding value is \(Q/\mathrm{BSA}\), with units L/h/m². These ratios answer different descriptive questions: how large is \(Q\) relative to each kilogram, or relative to each square metre of estimated body surface?

Indexing can make comparisons easier when the chosen denominator is appropriate, but it does not guarantee that the ratio is constant across people. For that stronger claim, evidence about the relationship between \(Q\) and the descriptor is needed. Nor does dividing an absolute quantity by a descriptor automatically tell a modeller which value to put into a PBPK model. The model’s structure and the source’s reporting basis must be considered.

Which Descriptor Is Commonly Used?

The choice depends on the quantity, its source, and the purpose of the comparison. There is no universal rule that every PBPK physiological input should be indexed to body mass, BSA, or LBM.

In PBPK work, a source may report a physiological quantity as an absolute value, per kilogram, or per square metre. Preserve that basis when extracting the value, and record the units and descriptor. If a model requires an absolute input but a source gives an indexed value, conversion requires the corresponding individual’s descriptor: for example, \(Q=(Q/W)W\). The calculation is only meaningful if the source’s per-kilogram definition and the selected body mass refer to compatible populations and conditions.

Height is most often an input to derived descriptors rather than a direct denominator. BSA is a common indexing basis in some clinical and physiological contexts, but it is not synonymous with body mass. LBM can be informative when the relevant process is expected to relate more closely to lean tissue than to total mass, yet an estimated LBM should not be substituted automatically for a source’s stated body-mass basis. These are choices of measurement basis, not claims that one metric is universally superior.

Assumptions, Diagnostics, and Limitations

Calculations are straightforward only when their inputs and definitions are consistent. Before using a value, check that mass and height units match the equation, the BSA formula is identified, and an LBM equation is applied in the population for which it is intended. Check whether the reported physiological quantity is absolute or indexed, and verify that its denominator is the same descriptor used in any conversion. A unit check often exposes errors: a quantity in L/h divided by kg must be in L/h/kg, not L/h/m².

A ratio can conceal important variation. If \(Q/W\) differs across individuals, that difference may reflect genuine physiology, measurement error, or a relationship between \(Q\) and body mass that is not proportional. A single indexed value cannot distinguish these explanations. Similarly, equations for BMI, BSA, and LBM summarize body characteristics; they do not directly measure organ function or establish how a particular PBPK parameter changes with size.

The principal alternatives are to report the absolute quantity with the individual’s body-size descriptors, or to report a normalized quantity using a clearly justified denominator. Absolute values preserve the measured scale and are useful for a specific individual; indexed values support comparisons on a stated basis. When the relationship between the quantity and size is the scientific question, a ratio should not be treated as proof of proportionality. The appropriate analysis or scaling model depends on that question and is beyond what a size descriptor alone can establish.

Practical Selection Sequence