PK PD Analysis Study: Foundation of your eCTD FDA Submission
PK PD analysis study links drug exposure to therapeutic effect measures so drug developers can better understand the relationships between exposure, efficacy, and toxicity. Thus, PK PD assay and data analysis results are essential to any ECTD submission. Pharmacokinetics (PK) parameters are typically calculated by non-compartmental analysis (NCA) following the determination of test article concentrations in samples from clinical or preclinical studies. Generally, area under the curve (AUC) and maximum concentration (Cmax, or C0 for an IV dose) are accepted as the most critical PK parameters when discussing exposure and activity or toxicity. AUC in pharmacokinetics represents the total exposure of the test article over the tested time course. AUC can be extrapolated to infinity for well-designed studies. We derive absolute or relative bioavailability (F%) from the AUCs of multiple dose groups or administration routes. Scientists can readily obtain the Volume of distribution (Vz) and Clearance (CL) from a single IV dose. We can calculate specific PK parameters such as Volume of distribution at steady-state (Vss) and mean residence time (MRT) related to steady-state pharmacokinetics from a single dose using pharmacokinetic equations using statistical moment analysis. Thus, pharmacokinetic parameters help ascertain dose levels for PK PD modeling of drug exposure and efficacy in preclinical models of human disease, evaluate the impact of dose proportionality (linear or non-linear pharmacokinetics) on efficacy, toxicity, and therapeutic index, assess appropriate dosing intervals, and estimate clearance time in the case of serious adverse events or dose-limiting toxicities.
Compartmental vs. Non-Compartmental Analysis (NCA)
PK PD modeling is performed using non-compartmental analyses (NCA) or compartmental analysis. NCA allows for a model-independent interpretation of pharmacokinetic data using pre-defined equations. For individual studies in preclinical discovery through clinical development, non-compartmental analyses are often employed to characterize the pharmacokinetic data, offering the advantages of consistency of data for interpretation across multiple studies without any assumptions about compartment numbers or behaviors. Alternatively, compartmental analysis involves selecting a discrete number of bodily compartments that are connected and homogenously mixed. Here, the rates of drug flow in and out of each compartment are quantifiable. Physiologically based pharmacokinetic (PBPK) models are the most complex compartmental analyses, where all relevant organs and bodily systems represent compartments in the kinetic model. Typically, compartmental studies are utilized in population PK analyses with specific objectives to compare patient demographics and aid in decisions regarding dosing levels and frequencies to reach appropriate steady-state concentrations of drug in the body for suitable efficacy and minimal toxicity in differing population covariates. In all cases, well-designed PK PD studies are essential to obtain relevant data analysis to properly determine reliable kinetic parameters for correlation to efficacy and toxicity. Preclinical PK PD analysis helps select dose levels and regimens for pharmacology efficacy testing, and PK PD modeling helps scale preclinical results for preliminary predictions of clinical pharmacokinetics.