Translatability of in vitro potency to clinical efficacious exposure: A retrospective analysis of FDA‐approved targeted small molecule oncology drugs

Abstract In vitro potency is one of the important parameters representing efficacy potential of drugs and commonly used as benchmark of efficacious exposure at early clinical development. There are limited numbers of studies which systematically investigate on how predictive in vitro potency is to estimate therapeutic drug exposure, especially those focusing on targeted anticancer agents despite the recent increase in approvals. This study aims to fill in such knowledge gaps. A total of 87 small molecule targeted drugs approved for oncology indication between 2001 and 2020 by the US Food and Drug Administration (FDA) were identified; relevant preclinical and clinical data were extracted from the public domain. Relationships between the in vitro potency and the therapeutic dose or exposure (unbound average drug concentration [Cu,av] as the primary exposure metrics) were assessed by descriptive analyses. The Spearman's rank correlation test showed slightly better correlation of the Cu,av (ρ = 0.232, p = 0.041) rather than the daily dose (ρ = 0.186, p = 0.096) with the in vitro potency. Better correlation was observed for the drugs for hematologic malignancies compared with those for solid tumors (root mean square error: 140 [n = 28] versus 297 [n = 59]). The present study shows that in vitro potency is predictive to estimate the therapeutic drug exposure to some extent, whereas the general trend of overexposure was observed. The results suggested that in vitro potency alone is not sufficient and robust enough to estimate the clinically efficacious exposure of molecularly targeted small molecule oncology drugs. The totality of data, including both nonclinical and clinical, needs to be considered for dose optimization.