Abstract
IntroductionFrom a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) 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 111In-CP04 in animal models, essential for the regulatory approval of the clinical trial. Materials and methodsAcute and extended single dose toxicity of CP04 was tested in rodents, while the in vivo stability of 111In-CP04 was assessed by HPLC analysis of mouse blood samples. The biodistribution of 111In-CP04 prepared from a freeze-dried kit was studied in SCID mice bearing double A431-CCK2R(±) xenografts at 1, 4 and 24h pi. Further 4-h animal groups were either additionally treated with the plasma expander gelofusine or injected with 111In-CP04 prepared by wet-labelling. Pharmacokinetics in healthy mice included the 30min, 1, 4, 24, 48 and 72h time points pi. Dosimetric calculations were based on extrapolation of mice data to humans adopting two scaling models. ResultsCP04 was well-tolerated by both mice and rats, with an LD50>178.5μg/kg body weight for mice and a NOAEL (no-observed-adverse-effect-level) of 89μg/kg body weight for rats. After labelling, 111In-CP04 remained >70% intact in peripheral mouse blood at 5min pi. The uptake of 111In-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 0.044mSv/MBq. ConclusionThe 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.
Highlights
From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111InDOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC)
The uptake of 111In-CP04 prepared from the freeze-dried kit and by wet-labelling were comparable in the A431-cholecystokinin subtype 2 receptors (CCK2R)(+)-xenografts (9.24 ± 1.35%ID/g and 8.49 ± 0.39%ID/g, respectively; P N 0.05)
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
Summary
From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, 111In-CP04 (111InDOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). 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. Molecular imaging and peptide receptor radionuclide therapy (PRRT) approaches can exploit the overexpression of cholecystokinin subtype 2 receptors (CCK2R) at an incidence of over 90% in MTC (Reubi et al, 1997; Reubi and Waser, 1996) This finding has motivated a number of research groups to develop site-specific radiolabeled analogues of cholecystokinin-8 (CCK-8; Asp-Tyr-Met-Gly-Trp-Met-AspPhe-NH2) or minigastrin (MG, Leu-(Glu)5-Ala-Tyr-Gly-Trp-Met-AspPhe-NH2). This finding has motivated a number of research groups to develop site-specific radiolabeled analogues of cholecystokinin-8 (CCK-8; Asp-Tyr-Met-Gly-Trp-Met-AspPhe-NH2) or minigastrin (MG, Leu-(Glu)5-Ala-Tyr-Gly-Trp-Met-AspPhe-NH2). (Behr and Behe, 2002; Froberg et al, 2009; Nock et al, 2005; Sosabowski et al, 2007; von Guggenberg et al, 2004; von Guggenberg et al, 2007)
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