PII-042 - TRANSLATABILITY OF IN VITRO POTENCY TO CLINICALLY EFFICACIOUS EXPOSURE FOR MOLECULARLY TARGETED SMALL MOLECULE ONCOLOGY DRUGS.

N. Kotani^1,2, K. Ito³; ¹Chugai Pharmaceutical Co., Ltd., Tokyo, Japan, ²Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan, ³Musashino University, Tokyo, Japan.

Background: In vitro potency is one of the important parameters representing efficacy potential of drugs. There are limited studies investigating how predictive in vitro potency is to estimate therapeutic drug exposure, especially those focusing on anticancer agents. This study aimed to investigate the translatability of in vitro potency to clinically efficacious exposure for molecularly targeted small molecule oncology drugs.

Methods: Molecularly targeted small molecule oncology drugs, approved between 2001 and 2020 by FDA, were identified from the list of “Compilation of CDER New Molecular Entity (NME) Drug and New Biologic Approvals”. Summary Basis of Approval and the latest label were obtained on the Drugs@FDA website, and reviewed to extract relevant clinical and pre-clinical data. Relationships between in vitro potency (IC50 against the target) and the therapeutic dose or exposure (average unbound drug concentration [Cu,av]) were assessed by a descriptive analysis.

Results: A total of 87 drugs were identified. Spearman’s rank correlation test showed slightly better correlation of Cu,av with IC50 (ρ = 0.226) compared with the therapeutic dose (ρ = 0.186). The higher correlation was observed for the drugs for hematologic malignancies (n=28) compared with those for solid tumors (n=59). Generally, Cu,av was higher than IC50, but 7 drugs showed notably low Cu,av (less than 1/10 of IC50).

Conclusion: This study showed that in vitro potency is predictive to estimate the therapeutic drug exposure to some extent, while general trend of overexposure was observed. The results suggested that in vitro potency based estimation of the clinically efficacious exposure is not sufficient and robust enough to justify dose optimization of molecularly targeted small molecule oncology drugs.