Pharmacokinetics (PK) is the study of the time course of the absorption, distribution, metabolism and excretion (ADME) of a drug, compound or new chemical entity (NCE) after its administration to the body. Following a brief introduction as to why knowledge of the PK properties of an NCE is critical to its selection as a lead candidate in a drug discovery program and/or its use as a functional research tool, the present article presents an overview of PK principles, including practical guidelines for conducting PK studies as well as the equations required for characterizing and understanding the PK of an NCE and its metabolite(s). A review of the determination of in vivo PK parameters by non-compartmental and compartmental methods is followed by a brief overview of allometric scaling. Compound absorption and permeability are discussed in the context of intestinal absorption and brain penetration. The volume of distribution and plasma protein and tissue binding are covered as is the clearance (systemic, hepatic, renal, biliary) of both small and large molecules. A section on metabolite kinetics describes how to estimate the PK parameters of a metabolite following administration of an NCE. Lastly, mathematical models used to describe pharmacodynamics (PD), the relationship between the NCE/compound concentration at the site of action and the resulting effect, are reviewed and linked to PK models in a section on PK/PD.

Since 2016, results from physiologically based pharmacokinetic (PBPK) analyses have been routinely found in the clinical pharmacology section of regulatory applications submitted to the US Food and Drug Administration (FDA). In 2018, the Food and Drug Administration's Office of Clinical Pharmacology published a commentary summarizing the application of PBPK modeling in the submissions it received between 2008 and 2017 and its impact on prescribing information. In this commentary, we provide an update on the application of PBPK modeling in submissions received between 2018 and 2019 and highlight a few notable examples.

In this study, we determined the pH and buffer capacity of human gastrointestinal (GI) fluids (aspirated from the stomach, duodenum, proximal jejunum, and mid/distal jejunum) as a function of time, from 37 healthy subjects after oral administration of an 800 mg immediate-release tablet of ibuprofen (reference listed drug; RLD) under typical prescribed bioequivalence (BE) study protocol conditions in both fasted and fed states (simulated by ingestion of a liquid meal). Simultaneously, motility was continuously monitored using water-perfused manometry. The time to appearance of phase III contractions (i.e., housekeeper wave) was monitored following administration of the ibuprofen tablet. Our results clearly demonstrated the dynamic change in pH as a function of time and, most significantly, the extremely low buffer capacity along the GI tract. The buffer capacity on average was 2.26 μmol/mL/ΔpH in fasted state (range: 0.26 and 6.32 μmol/mL/ΔpH) and 2.66 μmol/mL/ΔpH in fed state (range: 0.78 and 5.98 μmol/mL/ΔpH) throughout the entire upper GI tract (stomach, duodenum, and proximal and mid/distal jejunum). The implication of this very low buffer capacity of the human GI tract is profound for the oral delivery of both acidic and basic active pharmaceutical ingredients (APIs). An in vivo predictive dissolution method would require not only a bicarbonate buffer but also, more significantly, a low buffer capacity of dissolution media to reflect in vivo dissolution conditions.