Pharmacokinetics and Toxicokinetics

Abstract The evaluation of a compound's pharmacokinetics (PK) and toxicokinetics (TK) is one critical component in understanding how a drug works in vivo. In the 1990s, one of the primary reasons for the failure of early clinical studies was poor or inadequate PK in humans. Since then, drug discovery and development has incorporated early assessments of preclinical PK into the lead optimization stage. As a consequence, the current primary reasons for failures during clinical development are lack of efficacy and/or toxicity. Scaling of preclinical data (both in vitro and in vivo) now facilitates estimates of human pharmacokinetics prior to the initiation of clinical studies. When those estimates point toward unfavorable PK or doses required for efficacy, this becomes part of the decision process on whether or not to take a particular compound into the clinic. Once a compound is selected for clinical development, a fundamental understanding of the PK and the TK of the compound is necessary to evaluate drug exposures obtained in the toxicology studies, which ensure a safe initial starting dose for first-in-human studies. Moreover, the same knowledge is instrumental in determining dose and dose frequency when testing efficacy. Thus, a basic understanding of the principles of PK is necessary to meet the current clinical challenges of toxicity and efficacy. This chapter includes an introduction to commonly used PK and TK parameters, a comparison of the PK characteristics, and challenges associated with small versus large molecules, as well as some practical considerations for the interpretation of PK/TK data.