Pharmacometrics

Introduction & scope

• Definition — Pharmacometrics = the quantitative modelling & simulation of PK, PK-PD, exposure–response and disease-progression relationships to inform dosing and drug development. Pharmacokinetics is the quantitation of the time course of drug & metabolites and the building of models to describe and predict; pharmacodynamics is the relationship between systemic exposure and response.
• PK/PD modelling — Integrating a PK model with a PD model to capture the full relationship between drug administration and response over time is termed pharmacokinetic–pharmacodynamic (PK/PD) modelling — the core construct of the discipline.
• Central premise — The plasma (systemic) drug concentration serves as a useful correlate of response, because response of a systemically acting drug relates to the amount entering the body and its duration there, and direct measurement at the site of action (brain, heart) is rarely feasible.
• Why model — A model summarises data and facilitates extrapolation & prediction; despite the complexity of human physiology, even simple PK models have proved useful. Clinical pharmacokinetics provides a quantitative dose–effect relationship and a framework to interpret concentration measurements and adjust dosing.
• Applications — Modelling rationally (i) relates temporal patterns of efficacy & harm to dosing; (ii) underpins drug design, selection & regimen design; (iii) guides in-vivo protocol design & data interpretation; (iv) sets in-vitro dissolution specifications; (v) enables individualised dose initiation in patients.