Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with 111 In-CP04 in medullary thyroid carcinoma patients

Introduction From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111 In-CP04 ( 111 In-DOTA-(DGlu) 6 -Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH 2 ) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of 111 In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methods Acute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111 In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111 In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R(±) xenografts at 1, 4 and 24 h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with 111 In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30 min, 1, 4, 24, 48 and 72 h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models. Results CP04 was well-tolerated by both mice and rats, with an LD 50 > 178.5 μg/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89 μg/kg body weight for rats. After labelling, 111 In-CP04 remained > 70% intact in peripheral mouse blood at 5 min pi. The uptake of 111 In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-CCK2R(+)-xenografts (9.24 ± 1.35%ID/g and 8.49 ± 0.39%ID/g, respectively; P > 0.05). Gelofusine-treated mice exhibited significantly reduced kidneys values (1.69 ± 0.15%ID/g vs. 5.55 ± 0.94%ID/g in controls, P < 0.001). Dosimetry data revealed very comparable effective tumour doses for the two scaling models applied, of 0.045 and 0.044 mSv/MBq. Conclusion The present study has provided convincing toxicology, biodistribution and dosimetry data for prompt implementation of the freeze-dried kit formulation without or with gelofusine administration in a multicentre clinical trial in MTC patients.