title: Production of high specific activity (195m) Pt-cisplatinum at South African Nuclear Energy Corporation for Phase 0 clinical trials in healthy individual subjects.
abstract: 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 (195m) Pt-cisplatinum (commonly referred to as cisplatin) for a clinical pilot study on healthy volunteers. Enriched (194) PtCl2 was prepared by digestion of enriched (194) Pt metal (>95%) followed by thermal decomposition over a 3 h period. The (194) PtCl2 was then placed in a quartz ampoule, was irradiated in SAFARI-1 up to 200 h, then decay cooled for a minimum of 34 h prior to synthesis of final product. (195m) Pt(NH3 )2 I2 , formed with the addition of KI and NH4 OH, was converted to the diaqua species [(195m) Pt(NH3 )2 (H2 O)2 ](2+) by reaction with AgNO3 . The conversion to (195m) Pt-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 ± 2.5 MBq/mg at end of synthesis) than previously found (5 MBq/mg). Volunteers received between 108 and 126 MBq of radioactivity, which is equivalent to 6.8-10.0 mg of carrier cisplatinum. Such high specific activities afforded a significant reduction (~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 5 h post injection (p.i.). Only 8.5% ± 3.1% of cisplatinum remained in blood pools at 5 h, which gradually cleared over the 6-day monitoring period p.i. At the end of the study (6 days 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.
authors.affiliation: DST (Department of Science and Technology)/North West University Preclinical Drug Development Platform, North West University, 11 Hoffman St, Potchefstroom, 2520, South Africa.
authors.forename: Jan Rijn
authors.initials: JR
authors.lastname: Zeevaart
authors.forename: Judith
authors.initials: J
authors.lastname: Wagener
authors.forename: Biljana
authors.initials: B
authors.lastname: Marjanovic-Painter
authors.forename: Mike
authors.initials: M
authors.lastname: Sathekge
authors.forename: Nischal
authors.initials: N
authors.lastname: Soni
authors.forename: Christa
authors.initials: C
authors.lastname: Zinn
authors.forename: Gary
authors.initials: G
authors.lastname: Perkins
authors.forename: Suzanne V
authors.initials: SV
authors.lastname: Smith
mesh_terms: D002945:Cisplatin / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000652:urine; D064368:Healthy Volunteers; D006801:Humans; D010984:Platinum / Q000737:chemistry* / Q000493:pharmacokinetics*; D011854:Radiochemistry
chemical_list: D010984:Platinum; D002945:Cisplatin
keywords: 195mPt-cisplatinum; cisplatin; companion diagnostic; personalized medicine