A brief survey of first-in-human studies.
First-in-human (FIH) studies are a critical step in the drug development process and typically aim to characterize a compound's pharmacokinetics, potential effective concentration or dose, and safety or tolerability margins. Although effort continues to enhance the predictive quality of the selection of FIH doses from preclinical data, and little consensus is available on the design and conduct of FIH studies, detailed surveys describing general approaches taken in FIH studies are useful in the optimization of early-phase clinical drug development. Although allometric scaling techniques continue to provide poor predictive estimates for human pharmacokinetic parameters, FIH starting doses are selected with substantial safety factors applied to human equivalent dose, often in excess of regulatory guidelines. Based on these examples, it appears that relatively conservative 2-fold dose escalations are the most common escalation approach within FIH single ascending dose studies. The combination of conservative dose escalations with low starting doses can result in large FIH trials, consuming both time and resources. Approaches that could enhance the predictive nature of a compound's disposition and adaptive nature of FIH studies could provide a tremendous benefit for drug development.
Wexler
David
D
Pharmaceutical Research & Development, Johnson & Johnson, San Diego, CA 92121, USA.
Bertelsen
Kirk M
KM
D000818:Animals; D017321:Clinical Trials, Phase I as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D054796:Drug Dosage Calculations; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000633:toxicity; D006801:Humans; D019055:No-Observed-Adverse-Effect Level; D010865:Pilot Projects; D016032:Randomized Controlled Trials as Topic; D012107:Research Design; D013810:Therapeutic Equivalency
D015507:Drugs, Investigational