While providing a better simultaneous description of the three PK curves, scaling results in an intrinsic correlation between the parameters.
Pharmacokinetics (PK) considerations.
The core steps are (i) scale PK (only CL if steady-state concentrations required), (ii) translate pharmacology between species through unbound concentrations; if PD turnover required, scale by bodyweight to ¾ power; (iii) combine scaled PK and PD to produce a human dose prediction.
Allometric scaling has been successfully employed for small molecules to scale PK parameters from preclinical animal studies to humans using a BW-based power function with a fixed exponent of 0.75 for systemic metabolic clearance and an exponent of 1 for volume of distribution, although the use of a single fixed exponent value for scaling CL has been questioned.
Point estimates for the test/reference ratios and the corresponding 90% CIs were calculated using an analysis of variance (ANOVA) based on the logarithmic scale regarding PK parameters (multiplicative model) and on the original scale for PD parameters (additive model).
These models frequently employ simple allometric functions to scale a PK parameter (Y), such as clearance or volume of distribution, from adults to children using a body-weight (BW based power function (Y = a·BW b ) with a coefficient (a) and an exponent (b).
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For large molecules such as mAbs with nonlinear PK, assumptions underlying allometric scaling, such as the absence of nonlinear pharmacokinetics and species-specific clearance may not be correct.
The corresponding pKs values (in molality scale) for MgO, CaO and BaO, (respectively 9.0 ± 0.15, 5.0 ± 0.3, 2.31 ± 0.05) are compared, when possible, to those previously determined by other methods.
Large-scale population PK analyses conducted during the development of novel chemical entities are used to guide dose optimization and administration to provide maximal benefit to the patients.
These facilitate inclusive large-scale PK-PD assessments.
