Clinical pharmacokinetics of tumor necrosis factor antagonists.

Clinical pharmacokinetics of the 3 existing marketed tumor necrosis factor (TNF) antagonists, adalimumab (Abbott Laboratories), etanercept (Amgen, Inc.), and infliximab (Centocor, Inc.) are reviewed. The relevance and potential clinical implications of any differences in their pharmacokinetic properties are outlined. The major therapeutic goal when administering TNF antagonists is to eliminate the surplus of TNF from the circulation and from sites of inflammation. Within the causal chain of events after a drug is administered the exposure (or pharmacokinetics) precedes the effect (or pharmacodynamics). The differences in the observed concentration-time profiles and the exposure characteristics derived from them are induced either by differences of the inherent properties of the molecules (such as binding to various receptors, absorption and clearance mechanisms and rates, etc.), or by the differences in the dosage and administration regimens of the drugs (such as dose magnitude, administration frequency, route of administration, etc.). Review of the dose exposure-response cascade of the TNF antagonists shows that: (1) their pharmacokinetic properties should be interpreted in the context of the "therapeutic window" paradigm; and (2) exposure of tissues and fluids is a primary determinant of the drug action/adverse action. Therefore, efforts should be made to evaluate the pharmacokinetics of the TNF antagonists in such tissues/fluids of interest as the inflammation sites (e.g., synovium, gut mucosa, skin lesions) and sites of potential adverse effects (e.g., lungs).