Production of high specific activity ^195mPt‐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.

A Drug of Such Damned Nature.1 Challenges and Opportunities in Translational Platinum Drug Research

“…Studies reporting the preparation of [ 191 Pt]­cisplatin (1985) and [ 193m Pt]­cisplatin (1973) have received follow-up; [ 191 Pt]­cisplatin appears to have been intended partly as a radiotherapeutic pharmacologic form of cisplatin that did not progress into humans and partly for imaging (see below), and the [ 193m Pt]­cisplatin was not used for imaging. Multiple reports of preparations of [ 195m Pt]­cisplatin exist from 1973 onward, ,− and performance assessment showed that the minimum detection limit for a 2 cm tumor was 8 ppm …”

Radioactive Transition Metals for Imaging and Therapy

“…This is obviously not a simple process, especially in the context of working with a significant quantity of 195m Pt. Zeevaart et al recently published a variation on this procedure in which the starting material for the synthesis is irradiated 195m PtCl 2 . While this approach does avoid the stoichiometric reduction of Pt­(IV) to Pt­(II), it is still a multistep process.…”

Bringing Radiotracing to Titanium-Based Antineoplastics: Solid Phase Radiosynthesis, PET and ex Vivo Evaluation of Antitumor Agent [45Ti](salan)Ti(dipic)

“…Positron emission tomography (PET) addresses these concerns by non-invasively determining the concentrations of radiolabeled compounds as they distribute in vivo 16 . The similar technique of single photon computed tomography (SPECT) has recently been employed to clinically determine the distribution of [ 195m Pt]cisplatin in an effort to relate the pharmacokinetics to treatment efficacy 17 . Turning to Ti-based antineoplastics, implementation of PET and radiotracing early in preclinical development could aid in determining the mechanism of action, and evaluate dosing and drug formulation.…”