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BIOLOGICS |
From Pharmacokinetics, Modeling & Simulation, Clinical Pharmacology & Experimental Medicine, Centocor Research & Development, Malvern, Pennsylvania.
A formal assessment of the drug-drug interaction potential of any investigational drug product often requires multiple metabolic and pharmacokinetic evaluations. In contrast to a small-molecule drug, investigating the drug-drug interaction potential of a monoclonal antibody is inherently complicated. High molecular weight monoclonal antibodies are often genetically engineered to demonstrate strong specificity for a particular human antigen target. Consequently, monoclonal antibodies usually have few clinically relevant animal models—other than nonhuman primates—in which to conduct appropriate nonclinical studies. Likewise, clinical drug-drug interaction studies of monoclonal antibodies with long elimination half-lives pose definite operational challenges as conventional crossover studies with adequate washout periods are difficult to conduct. Furthermore, the current regulatory guidance on the design and conduct of in vitro and in vivo drug-drug interaction studies applies more readily to small-molecule drugs than protein-based biologics. Nevertheless, a certain amount of clinically useful information has begun to emerge from the published literature on drug-drug interaction potentials of therapeutic monoclonal antibodies. This article provides a systematic review of the current literature and offers some practical considerations for the design and conduct of pharmacokinetic drug-drug interaction assessments involving novel monoclonal antibodies. Ideally, these evaluations should be performed throughout all stages of drug development. In particular, pharmacokinetic interaction studies with any marketed drugs that are likely to be coadministered with the monoclonal antibody will yield the most clinically useful information for practitioners and patients alike.
Key Words: Drug-drug interaction • biologics
Address for correspondence: Honghui Zhou, PhD, FCP, Pharmacokinetics, Modeling & Simulation, Clinical Pharmacology & Experimental Medicine, Centocor Research & Development, 200 Great Valley Parkway, Malvern, PA 19355; e-mail: hzhou2{at}cntus.jnj.com.
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