A. Hamada, K. Yonemori, T. Shimoi, S. Shimma, S. Osawa, Y. Tanabe, J. Hashimoto, M. Kodaira, H. Yamamoto, M. Yunokawa, C. Shimizu, Y. Fujiwara, K. Tamura; National Cancer Center, Tokyo, Japan
BACKGROUND: Assessment of drug pharmacokinetics is an important component of early phase drug development. Imaging Mass Spectrometry (IMS) is an innovative technique in clinical pharmacology that allows for analysis of the distribution of target molecules in tumor cells. The advantage of IMS is the detection of the molecule of interest in tissues without any labeling. We performed tumor biopsies in patients with solid tumors who were participating in a Phase I trial of olaparib. The aim of the present study was to examine drug distribution in the tumor specimens by IMS.
METHODS: Patients with solid tumors received olaparib tablet in dose escalation (200 mg BID, 300 mg BID) and expansion cohorts (300 mg BID). Biopsies were performed in consenting patients during cycle 2 and/or at the time of progression. IMS was performed using an Imaging Mass Microscope (Shimadzu, Japan). The concentrations of olaparib in tumor specimens were validated by LC-MS/MS method.
RESULTS: In total, 7 tumor biopsies were performed in 6 patients with solid tumors; 3 breast cancer including one BRCA1 mutation positive, 1 ovarian cancer, 1 peritoneal cancer, 1 cervical cancer. One patient with breast cancer had biopsies performed at the time of drug administration and at progression. IMS signals of olaparib correlated well with the concentration of drug in tumor tissues derived from patients using LC-MS/MS. Olaparib was distributed throughout the tumor region. The signal level of olaparib in necrosis cells was higher than that in living tumor cell.
CONCLUSION: We have successfully analyzed the micro-level distribution of an unlabeled olaparib in vitro by IMS. This technique may also allow further understanding of PK/PD relationships for olaparib when dosed in combination with other compounds in future clinical trials.