Pharmacometry

Pharmacometrics is the science of quantitative clinical pharmacology. Pharmacology studies the interaction between our body and the drug, this term designating "any substance or composition [...] exerting a pharmacological, immunological or metabolic action" (article L. 5111-1 of the French Public Health Code). This two-way interaction covers pharmacokinetics (PK), what our body does to the drug, and pharmacodynamics (PD), what the drug does to our body.

PK is mainly studied through the evolution of concentration as a function of time, often summarized by parameters such as the area under the curve (AUC), measuring total exposure, and the half-life, defined as the time required to halve the amount of drug in the system.

PD activity, on the other hand, is more diverse in nature. The markers of this activity depend on whether the response under consideration is biological or clinical, continuous or discrete. The joint study of a drug's PK and PD makes it possible to define the therapeutic margin between the minimum and maximum doses or concentrations required to observe a level of response that is respectively effective and toxic.

PK/PD markers are collected during drug development in healthy volunteers in Phase I, then in patients in Phase II, with a focus on toxicity and efficacy respectively. From phase II through to clinical routine, inter-subject or inter-individual variability is quantified and explored, so as to define its sources and assess the need for personalized treatment through dose and/or dosage.

Pharmacometrics encompasses techniques for characterizing PK and PD activity, and the extent to which this activity varies from one subject and/or occasion to another, as well as for predicting and simulating these activities in order to provide rational criteria for decision-making. This discipline has taken off in recent decades, with the development of so-called "population" methods, based on the use of non-linear mixed-effects models. These methods contrast with the two-stage analyses previously used: markers of PK and PD activity were estimated individually, then their mean value and variability calculated. Individual estimation requires a high number of samples per subject, and can only be used in early studies during clinical development. In later studies, where the number of patients is larger but the number of samples per patient smaller, or in fragile populations (immunocompromised patients, the elderly, patients with concomitant pathologies, children...), where the number of samples must remain minimal, population-based approaches enable all observations to be analyzed simultaneously, and use subjects with more samples to infer less informative subjects, based on statistical and mechanistic hypotheses....