Radium-223 chloride, a first-in-class alpha-pharmaceutical for patients with castration resistant prostate cancer (CRPC) and bone metastases. Dosimetry and pharmacokinetic analysis

Objectives Radium-223 chloride (Alpharadin) is a first-in-class targeted alpha- pharmaceutical with a potent and highly targeted antitumor effect on bone metastases and a benign safety profile. We evaluated the biodistribution and dosimetry of this agent in the context of its clinical safety profile.

Methods 6 patients with bone-metastatic CRPC received 2 doses of 100 kBq/kg 6 weeks apart. Blood, urine and faeces were collected before and at regular intervals after injection. Planar whole body quantitative gamma camera imaging determined biodistribution. Radiation dose was calculated with adjustments for GI tract, heart wall, red marrow (RM) and osteogenic cells (OC). It was also taken into consideration that the product emits short range, high energy alpha particles. Safety and tolerability were evaluated separately in 292 patients in Phase I/II trials treated with activities from 5 - 250 kBq/kg (single and multiple doses).

Results The biodistribution study showed that Radium-223 was rapidly eliminated from blood and taken up in bone (~60% at 4hr) or excreted into the small intestine. There was <5% urinary and no hepato-biliary excretion. Highest calculated absorbed doses were to OC, RM and lower large intestine wall: 1.6, 0.2 and 0.05 Gy/MBq, respectively. Among 292 heavily pre-treated patients, <1% had CTC grade 4 hematological toxicity and 2-4% had grade 3 toxicity for Hb, platelets or WBC. Mainly mild to moderate and reversible AEs were seen in the GI tract.

Conclusions Radium-223 chloride was rapidly sequestered to bone/bone metastases and excreted predominantly via the GI tract. The favourable haematological toxicity profile offers a clinically relevant advantage compared to beta radiopharmaceuticals, and is consistent with the short range of alpha particles