Production of high specific activity Pt-195m-cisplatinum at South African Nuclear Energy Corporation for Phase 0 clinical trials in healthy individual subjects

摘要

Platinum agents continue to be the main chemotherapeutic agents used in the first-line and second-line treatments of cancer patients. It is important to fully understand the biological profile of these compounds in order to optimize the dose given to each patient. In a joint project with the Australian Nuclear Science and Technology Organisation and the Nuclear Medicine Department at Steve Biko Academic Hospital, South African Nuclear Energy Corporation synthesized and supplied Pt-195m-cisplatinum (commonly referred to as cisplatin) for a clinical pilot study on healthy volunteers. Enriched (PtCl2)-Pt-194 was prepared by digestion of enriched Pt-194 metal (>95%) followed by thermal decomposition over a 3h period. The (PtCl2)-Pt-194 was then placed in a quartz ampoule, was irradiated in SAFARI-1 up to 200h, then decay cooled for a minimum of 34h prior to synthesis of final product. Pt-195m(NH3)(2)I-2, formed with the addition of KI and NH4OH, was converted to the diaqua species [Pt-195m(NH3)(2)(H2O)(2)](2+) by reaction with AgNO3. The conversion to Pt-195m-cisplatinum was completed by the addition of concentrated HCl. The final product yield was 51.7%5.2% (n=5). The chemical and radionuclidic purity in each case was >95%. The use of a high flux reactor position affords a higher specific activity product (15.9 +/- 2.5MBq/mg at end of synthesis) than previously found (5MBq/mg). Volunteers received between 108 and 126MBq of radioactivity, which is equivalent to 6.8-10.0mg of carrier cisplatinum. Such high specific activities afforded a significant reduction (similar to 50%) in the chemical dose of a carrier cisplatinum, which represents less than 10% of a typical chemotherapeutic dose given to patients. A good manufacturing practice GMP compliant product was produced and was administered to 10 healthy volunteers as part of an ethically approved Phase 0 clinical trial. The majority of the injected activity 27.5%+/- 5.8% was excreted in the urine within 5h post injection (p.i.). Only 8.5%+/- 3.1% of cisplatinum remained in blood pools at 5h, which gradually cleared over the 6-day monitoring period p.i. At the end of the study (6days p.i.), a total of 37.4%+/- 5.3% of the product had cleared from the blood into urine, and approximately 63% remained in the body. The significantly lower concentration of carrier cisplatinum used for imaging resulted in a well-tolerated product. Copyright (c) 2013 John Wiley & Sons, Ltd.