Phase I pharmacokinetic and biodistribution study with escalating doses of ²²³Ra-dichloride in men with castration-resistant metastatic prostate cancer

Abstract

Purpose: ²²³Ra-Dichloride (²²³Ra) is a novel bone-seeking alpha-emitter that prolongs survival in patients with castration-resistant metastatic prostate cancer. We conducted a study to better profile the pharmacokinetics, pharmacodynamics, and biodistribution of this agent.

Methods: Ten patients received either 50, 100, or 200 kBq of ²²³Ra per kilogram of body weight. Subsequently, six of these ten patients received a second dose of 50 kBq/kg. Pharmacokinetics and biodistribution were assessed by serial blood sampling, planar imaging, and whole-body counting. Pharmacodynamic assessment was based on measurements of prostate-specific antigen, bone alkaline phosphatase, and serum N-telopeptide. Safety was also assessed.

Results: Pharmacokinetic studies showed rapid clearance of ²²³Ra from the vasculature, with a median of 14% (range 9-34%), 2% (range 1.6-3.9%), and 0.5% (range 0.4-1.0%) remaining in plasma at the end of infusion, after 4 h, and after 24 h, respectively. Biodistribution studies showed early passage into the small bowel and subsequent fecal excretion with a median of 52% of administered ²²³Ra in the bowel at 24 h. Urinary excretion was relatively minor (median of 4% of administered ²²³Ra). Bone retention was prolonged. No dose-limiting toxicity was observed. Pharmacodynamic effects were observed (alkaline phosphatase and serum N-telopeptides) in a significant fraction of patients.

Conclusion: ²²³Ra cleared rapidly from plasma and rapidly transited into small bowel, with fecal excretion the major route of elimination. Administered activities up to 200 kBq/kg were associated with few side effects and appeared to induce a decline in serum indicators of bone turnover.

Conflict of interest statement

Conflicts of interest Jorge A. Carrasquillo, John L. Humm and Joseph A. O’Donoghue consult for Algeta ASA. Anne-Kirsti Aksnes is an employee of Algeta ASA. All other authors declare they have no conflict of interest.

Figures

Fig. 1

Decay-corrected percentage of 223Ra retained in the whole body (initial pre-void counts taken as 100 %) in patients (n=8) over a period of approximately 1 week post-administration

Fig. 2

Serial dynamic images of anterior abdomen/pelvis obtained after intravenous administration of 7,585 kBq (0.205 mCi) of 223Ra-dichloride (patient 4). The images show prompt uptake throughout small bowel with mild uptake in liver and no gallbladder visualization. The uptake in small bowel, although showing some changes, persists for 232 min. The activity moves intraluminally into ascending and transverse colon (1 day), then into descending colon (2 days), and there is significant clearing from bowel by 6 days. The volume-rendered contrast CT shows bowel loops that correspond to the early 223Ra-chloride images. A 99mTc-MDP bone scan is available for reference. There is prompt uptake in the bone metastasis that persists and improves in contrast over time. Small amount of liver uptake is noted in the early dynamic images, but resolves in the later images

Fig. 3

Whole-body bone scan in left panel shows multiple metastatic disease to bone. 223Ra whole-body bone scan in right panel was taken 1 day after injection. Although 223Ra images have lower counts and are noisier than the bone scan, they clearly show focal accumulation in the most obvious bone metastasis, e.g., left distal femur, right femur, left proximal humerus. In addition, excretion into the ascending and transverse colon is noted

Fig. 4

Representative biodistribution images. Serial posterior images following injection of 4,366 kBq (0.118 mCi) of 223Ra-dichloride show initial accumulation in bone metastasis and normal bone that persists over time, compared to posterior 99mTc-MDP bone scan spot image of the same region. Early images will often show some mild uptake in the kidneys that decreases rapidly and is barely seen at 4 h and not seen beyond 1 day