For treatment of chronic cancers, the oral administration route is preferred as it provides numerous advantages over other delivery routes. However, these benefits of oral chemotherapy can be limited due to unfavorable pharmacokinetics. Accordingly, pharmacokinetic development of chemotherapeutic agents is crucial to the improvement of cancer treatment. In this study, assessment and optimization of biopharmaceutical properties of a promising drug candidate for cyclin-dependent kinase 9 (CDK9) inhibitor (DF030263) was performed to promote oral delivery. Oral bioavailability of DF030263 in fasted rats was 23.8%, and a distinct double-peak phenomenon was observed. A two-site absorption windows mechanism was proposed as a possible explanation to the phenomenon. The two-site absorption window hypothesis was supported by in vitro solubility assays in biorelevant fluids with different pH levels, as well as by in silico simulation by GastroPlus™. Controlled release to the colon was conducted in rats in order to exploit the colonic absorption window but did not improve the oral bioavailability. On the other hand, oral administration at postprandial conditions in rats (performed based on the high in vitro solubility in fed state simulated fluid and reduced pH-dependency) resulted in an almost 3-fold increase in bioavailability to 63.6%. In conclusion, this study demonstrates an efficient in vitro-in vivo-in silico drug development approach for improving the oral bioavailability of DF030263, a promising candidate for the treatment of chronic lymphocytic leukemia.

By Jong BongLee, Xiaowei Zang, Atheer Zgaira, Ting Qian Ooi, David W. Foley, Gregory Voronin, Leonid Kagan, Fadi Soukarieh, Rui Gao, Hao Shaoa, Wan Tying Soh, Tae Hwan Kim, Min Gi Kim, Hwi-yeol Yun, Anthony J. Wilson, Peter M. Fischer, Pavel Gershkovich