Pharmacokinetics of single dose radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases

Abstract

Objective: This open-label, non-randomized, phase I study examined the pharmacokinetics (PK) and radiation dosimetry of a single dose of radium-223 in Japanese patients with castration-resistant prostate cancer (CRPC) and bone metastases.

Methods: Six male Japanese patients (mean age 72.5 years, range 65-79 years) with histologically or cytologically confirmed stage IV adenocarcinoma of the prostate were recruited. A single IV dose of radium-223 was delivered intravenously (IV) via slow bolus over a 2-5 min period: Cohort 1 received 50 kBq/kg and Cohort 2 received 100 kBq/kg.

Results: Following IV injection, radium-223 was rapidly eliminated from the blood in a multi-phasic manner. The fraction of the injected activity of radium-223 retained in the whole body 24 h following injection was 85 %. Biodistribution results showed initial bone uptake was 52 % (range 41-57 %). The maximum activity of radium-223 in the bone was observed within 2 h of dosing. Activity of radium-223 passed through the small intestine within 24 h. No activity was detected in other organs. The major radiation dose from radium-223 was found in osteogenic cells; calculated absorbed doses in osteogenic cells and in the red marrow were 0.76 Gy/MBq and 0.09 Gy/MBq, respectively.

Conclusions: In Japanese patients with CRPC and bone metastases, radium-223 (IV) achieved maximum activity in the bone rapidly and passed through the intestine within 24 h, without signs of activity in other organs. The PK profile and absorbed radiation dose in organs and tissues in Japanese patients were similar to data from non-Japanese patients. Trial registration identification: NCT01565746.

Keywords: Castration-resistant prostate cancer; Metastases; Pharmacokinetics; Radium-223.

Fig. 1

Biodistribution of activity, as detected via gamma camera, of radium-223 over time in patient #4

Fig. 2

Pharmacokinetic profiles of activity concentration in blood after single injection of radium-223. The dosing arm 50 and 100 kBq/kg are 55 and 110 kBq/kg after implementation of NIST update [12], respectively

Fig. 3

Arithmetic mean percentage (standard deviation) of the cumulative activity excreted after injection of radium-223 in the a urine and b feces as a proportion of the injected dose. Fraction of injected activity represents the proportion of radioactivity (as a proportion of the injected dose) that was detected at various time points. Patients 1–3 received 50 kBq/kg (55 kBq/kg after the NIST update [12]) and patients 4–6 received 100 kBq/kg (110 kBq/kg after the NIST update [12])

Fig. 4

Fraction of injected activity in a the whole body and b the bone after injection of radium-223. Fraction of injected activity represents the proportion of radioactivity (as a proportion of the injected dose) that was detected at various time points. Patients 1–3 received 50 kBq/kg (55 kBq/kg after the NIST update [12]) and patients 4–6 received 100 kBq/kg (110 kBq/kg after the NIST update [12])

Fig. 5

Fraction of drug activity in the a small, b upper large and c lower large intestines over time after injection of radium-223. Fraction of injected activity represents the proportion of radioactivity (as a proportion of the injected dose) that was detected at various time points. Patients 1–3 received 50 kBq/kg (55 kBq/kg after the NIST update [12]) and patients 4–6 received 100 kBq/kg (110 kBq/kg after the NIST update [12])