C. Oo,1 Y. Cao,1 L. Lee,1 L. S. Lee2; 1Gatheringhill Court, Morris Plains, NJ, 2National University of Singapore, Singapore, Singapore
BACKGROUND: In drug development, a highest feasible dose is thought to deliver a maximum (or limiting) efficacy. This dogma is being challenged in the case of an inverted U-shaped dose response (USDR) characterized by low dose stimulation and high dose inhibition. In reality, USDR has been reported in biological systems, especially for neurotransmitters and hormones. Due to its broad implication, the occurrence of USDR was evaluated.
METHODS: Existing PubMed terms of “USDR” and “dose response curve” (DRC) of completed years 1975 to 2013 were searched. The numbers of articles from toxicology journals (containing ‘toxicol’ phrase) and those of the remaining articles were assessed. The increases in the numbers of articles over time were extrapolated based on an article from Larsen PO et al., 2010.
RESULTS: During 9 or 10-year intervals from 1975 to 2013, the numbers of articles per year for “USDR” were: <=6 (1975-1983), <=18 (1984-1993), <=32 (1994-2003), and <=44 (2004-2013). After reaching a sharp peak, the number of toxicology articles reported in year 2008 (13) declined to a regular baseline level in 2013 (2). The numbers of other articles reported annually (25 to 31) were consistent from years 2008 to 2013, and were mainly from the fields of neuroendocrinology and behavioral science. The total number of articles for “USDR” (665) constituted 3% of that for the general “DRC” (22,371). Time-adjusted data were not used due to small differences from the observed values (<=21%).
CONCLUSION: “USDR” was reported in the literature, albeit less frequently than for “DRC.” The actual occurrence of USDR is thought to be higher if there is a greater awareness. Recently, this finding is particularly applicable for lead candidates that are highly modulated or involving multiple receptor subtypes of opposing actions.