药代动力学与药效研究建模

references/special-populations.md

Size is not maturation

The helper uses CL=CLref*(WT/WTref)^b and an optional sigmoidal postmenstrual-age multiplier. The default b=0.75 for clearance and 1 for volume are modeling conventions, not universal biological laws. Drug/pathway-specific ontogeny, disease, organ function and binding can change the relation. Generic TM50/Hill values are illustrative; justify them before predicting neonatal exposure. Maturation of volume is not implemented by the helper's clearance-only multiplier.

A log-log interspecies slope estimates an association conditional on species/data selection. Small-sample intervals use t degrees of freedom, but that does not resolve species relevance, protein binding, transporter differences or nonlinear kinetics. Report the species, weight, clearance basis, assay, uncertainty and extrapolation range. Do not turn an exponent cutoff into a automatic correction method.

Pediatrics and organ function

ICH E11A asks how disease, pharmacology and treatment response support extrapolation between reference and target populations. Exposure matching can be appropriate with supporting evidence; 80–125% is not a universal pediatric acceptance requirement. Prespecify justified exposure criteria, uncertainty and safety evaluation for the intended population. E11A FDA guidance.

Renal-function measures differ by equation and indexing. Creatinine clearance, eGFR indexed to 1.73m² and absolute mL/min are not interchangeable. Likewise, hepatic impairment is not fully summarized by one enzyme value. Changing physiology, dialysis and critical illness need models that represent those mechanisms and time courses; weight scaling alone is insufficient.

Starting-dose arithmetic

The FDA 2005 healthy-adult framework uses NOAEL, species relevance, human-equivalent dose and a safety factor. The helper applies its Km table and reports the calculation, not clinical safety. Verify the species/body-weight applicability and exposure margins; additional uncertainty can need a larger safety factor. FDA starting-dose guidance.

MABEL reasoning integrates target biology, species relevance, binding/function, human cell data, PK and uncertainty. It is not simply choosing the smaller of two calculator outputs. The helper's --mabel inverts an Emax or equilibrium occupancy curve at a requested fractional effect, then multiplies concentration by clearance (systemic F=1 assumption) to give a dose rate. Functional EC50 is not generally binding Kd. Dose rate is not a bolus starting dose; duration/regimen and absorption are additional assumptions. High-risk agonism and complex biologics can invalidate this simple relationship. EMA first-in-human revision.