Clinical pharmacokinetics of TNF antagonists: how do they differ?

The relationship between the dose administered and the observed beneficial or adverse effects of a drug is one of the basic concepts of clinical pharmacology. The broad term "exposure" usually refers to the dose and the various acute or integrated measures of the resulting concentrations in blood (plasma, serum) and/or tissues/fluids. The term "response" refers to any direct measure of the pharmacologic effect (beneficial or otherwise) of the drug. Thus, as specified in a recent US Food and Drug Administration (FDA) Guidance for Industry (2004), "... a drug can be determined to be safe and effective only when the relationship of beneficial and adverse effect to a defined exposure is known." Consequently, there has been a recent strong academic, industrial, and regulatory interest in exploring and characterizing the exposure-response relationships of existing and developed drugs. The first part of the cascade exposure, response cascade, is the relationship between the administered dose and the observed concentration-time profiles in the organism of interest, often referred to as pharmacokinetics (PK). The second part is the relationship between the concentration levels and the observed pharmacodynamic (PD) responses, often called PK-PD relationship. Within the causal chain of events after a drug is administered, the exposure (or PK) precedes the effect (or PD). Therefore, whenever any differentiation in the beneficial and/or adverse effects between drugs with similar mechanisms of action is observed, the underlying clinical PK is among the first considerations. The purpose of the current article is to review the PK properties of the 3 existing marketed tumor necrosis factor (TNF) antagonists, adalimumab (Abbott Laboratories), etanercept (Amgen Inc.), and infliximab (Centocor, Inc.), and to discuss the potential clinical implications of any PK differences.