Pharmacokinetic/pharmacodynamic (PK/PD) modeling quantitatively links drug exposure to pharmacological response. Pharmacokinetics (PK) describes what the body does to the drug: absorption, distribution, metabolism, and excretion. Pharmacodynamics (PD) describes what the drug does to the body: the relationship between concentration at the site of action and the observed effect.
Compartmental PK models describe the body as one or more interconnected compartments. A one-compartment model assumes instantaneous distribution throughout the body. Two-compartment models separate central and peripheral compartments. Model parameters include volume of distribution, clearance, absorption rate constant, and bioavailability. Non-compartmental analysis estimates these parameters directly from the concentration-time curve without assuming a specific compartmental structure.
PK/PD models link the PK model to a PD model that describes the concentration-effect relationship. Direct link models assume that the effect is proportional to the plasma concentration. Indirect link models use an effect compartment to account for distribution delay to the site of action. Indirect response models describe effects resulting from inhibition or stimulation of production or dissipation of a physiological mediator.
The Hill equation (sigmoid Emax model) describes the concentration-effect relationship with parameters for baseline effect, maximum effect, concentration producing 50% of maximum effect, and the sigmoidicity factor. The turnover model describes the time course of biomarkers and clinical endpoints.
Population PK/PD modeling using nonlinear mixed effects modeling quantifies both typical values and inter-individual variability. Covariates such as body weight, age, renal function, and genetic polymorphisms explain sources of variability. The model is developed using iterative cycles of model building, diagnostics, and external validation.
Applications of PK/PD modeling include first-in-human dose selection, dose regimen optimization, food-effect assessment, drug-drug interaction prediction, and pediatric dose extrapolation. Physiologically based pharmacokinetic (PBPK) modeling incorporates physiological parameters to predict PK in special populations and enable in vitro to in vivo extrapolation.
Regulatory agencies increasingly expect PK/PD modeling to support dose selection and provide evidence of efficacy and safety throughout drug development. Model-informed drug development uses quantitative approaches to improve decision-making and reduce development timelines.
