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Process validation, current good manufacturing practice production, dosimetry, and toxicity studies of the carbonic anhydrase IX imaging agent [ 111 In]In‐XYIMSR‐01 for phase I regulatory approval
Author(s) -
De Silva Ravindra A.,
Gorin Michael A.,
Mease Ronnie C.,
Minn Il,
Lisok Ala,
Plyku Donika,
Nimmagadda Sridhar,
Allaf Mohamad E.,
Yang Xing,
Sgouros George,
Rowe Steven P.,
Pomper Martin G.
Publication year - 2021
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3906
Subject(s) - dosimetry , toxicity , internal dosimetry , chemistry , nuclear medicine , effective dose (radiation) , pharmacology , medicine , organic chemistry
[ 111 In]In‐XYIMSR‐01 is a promising single‐photon emission computed tomography (SPECT) imaging agent for identification of tumors that overexpress carbonic anhydrase IX. To translate [ 111 In]In‐XYIMSR‐01 to phase I trials, we performed animal toxicity and dosimetry studies, determined the maximum dose for human use, and completed the chemistry, manufacturing, and controls component of a standard regulatory application. The production process, quality control testing, stability studies, and specifications for sterile drug product release were based on United States Pharmacopeia chapters <823> and <825>, FDA 21 CFR Part 212. Toxicity was evaluated by using nonradioactive [ 113/115 In]In‐XYIMSR‐01 according to 21 CFR Part 58 guidelines. Organ Level INternal Dose Assessment/EXponential Modeling (OLINDA/EXM) was used to calculate the maximum single dose for human studies. Three process validation runs at starting radioactivities of ~800 MBq were completed with a minimum concentration of 407 MBq/ml and radiochemical purity of ≥99% at the end of synthesis. A single intravenous dose of 55 μg/ml of [ 113/115 In]In‐XYIMSR‐01 was well tolerated in male and female Sprague–Dawley rats. The calculated maximum single dose for human injection from dosimetry studies was 390.35 MBq of [ 111 In]In‐XYIMSR‐01. We have completed toxicity and dosimetry studies as well as validated a manufacturing process to test [ 111 In]In‐XYIMSR‐01 in a phase I clinical trial.