Pharmacometrics

Pharmacometrics

1. Definition, scope & rationale

• Pharmacokinetics is the quantitation of the time course of a drug and its metabolites in the body and the development of appropriate models to describe observations and predict outcomes in other situations (R&T 5e Ch.2, p.29). KDT frames it identically as "the quantitative study of drug movement in, through and out of the body" (KDT 8e Ch.2, p.15).
• Pharmacodynamics is the relationship between systemic exposure and response; 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 (R&T 5e Ch.2, pp.33–34).
• Pharmacometrics, as a discipline, is the quantitative modelling & simulation of these PK, PK-PD, exposure–response and disease-progression relationships to inform dosing and drug development. The foundational PK/PD chapters supply its building blocks — structural models, exposure–response equations and the variability framework — while the named specialist machinery of the field (nonlinear mixed-effects population PK, PBPK as a formal sub-discipline, and the model-informed drug-development [MIDD] regulatory framework) is developed in the Recent Advances chapter below with primary-source citations.
• The applications of PK & PD in drug therapy (the rationale for modelling) are enumerated as a discrete list (R&T 5e Ch.2, Table 2-1, p.20): (i) relate temporal patterns of response — efficacy and harm — to drug administration after acute and chronic dosing; (ii) provide a rational basis for drug design, drug selection, and dosage-regimen design; (iii) aid the design of in-vivo evaluation protocols and the interpretation of the data; (iv) evaluate drug-product performance in vivo and set in-vitro dissolution specifications; (v) provide a means for rationally initiating and individualising drug administration in patients.
• The central premise that licenses the whole modelling enterprise: the plasma (systemic) drug concentration serves as a useful correlate of response, because the response of a systemically acting drug is related to the amount entering the body and its duration there, and direct measurement at the site of action (brain, heart) is rarely feasible (R&T 5e Ch.2, p.20; p.33).
• Clinical pharmacokinetics seeks to provide (a) a quantitative relationship between dose and effect and (b) a framework within which to interpret drug-concentration measurements and adjust dosing for patient benefit (G&G 14e Ch.2, p.32).
• A model is useful to summarise data and facilitate extrapolation and prediction after drug administration; despite the complexity of human anatomy and physiology, simple PK models have proved useful in many applications (R&T 5e Ch.2, p.28).