225Ac-DOTA-Substance P as a potential radiopharmaceutical for targeted alpha therapy of glioblastoma multiforme

Gliomas, particularly WHO grade IV glioblastoma multiforme (GBM) are one of the most common and aggressive primary types of the cancer of the central nervous system and are composed of morphologically diverse population of cells in the tumour mass. Despite all current forms of treatment such as advanced surgery techniques, radiation therapy and chemotherapy, the life expectancy of patients diagnosed with GBM is 12 to 15 months displaying the worst median overall survival among all human neoplasms. Targeted alpha therapy has been shown to overcome chemo- and radioresistance in vitro and thus presents a promising new approach for therapy of GBM. The findings that high affinity Substance P receptor NK1 is high consistently expressed in primary malignant gliomas and in the intratumoral and peritumoral vasculature makes this receptor a very attractive target for glioma cancer therapy.JRC.G.I.5-Advanced Nuclear Knowledg

In vitro evaluation of 225Ac-DOTA-Substance P for targeted alpha therapy of glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with dismal prognosis despite treatment by surgery combined with radiotherapy and chemotherapy. The neuropeptide Substance P (SP) is the physiological ligand of the neurokinin‐1 receptor, which is highly expressed in glioblastoma cells. Thus, SP represents a potential ligand for targeted alpha therapy. In this study, a protocol for the synthesis of SP labeled with the alpha emitter 225Ac was developed and binding affinity properties were determined. The effects of 225Ac‐DOTA‐SP were investigated on human glioblastoma cell lines (T98G, U87MG, U138MG) as well as GBM stem cells. A significant dose‐dependent reduction in cell viability was detected up to 6 days after treatment. Also, colony‐forming capacity was inhibited at the lower doses tested. In comparison, treatment with the conventional agent temozolomide showed higher cell viability and colony‐forming capacity. 225Ac‐DOTA‐SP treatment caused induction of late apoptosis pathways. Cells were arrested to G2/M‐phase upon treatment. Increasing doses and treatment time caused additional S‐phase arrest. Similar results were obtained using human glioblastoma stem cells, known to show radioresistance. Our data suggest that 225Ac‐DOTA‐SP is a promising compound for treatment of GBM.JRC.G.I.5-Advanced Nuclear Knowledg

Evaluation of a Proposed Approach for the Determination of the Bioequivalence Acceptance Range for Narrow Therapeutic Index Drugs in the European Union

Bioequivalence (BE) of products containing narrow therapeutic index (NTI) drugs in the European Union is currently established by demonstrating that the 90% confidence interval for the ratio of the population geometric means of the test compared to the reference product’s AUC, and in certain cases Cmax, is included within the tighter acceptance range of 90.00–111.11%. An alternative criterion, consisting of narrowed limits based on the within-subject variability of the reference product, was recently proposed. Its performance for a three-period partial replicate design was tested by simulation in terms of power to show BE, type I error (T1E) and sample size requirements. A new condition, a constraint on the test-to-reference geometric mean ratio (cGMR) to be contained within the range of 90.00–111.11%, was also tested. The probability of showing BE when the products differ more than 10% was increased, but only if the reference product’s within-subject variability was moderate-to-high. The inclusion of the additional cGMR limited this. An increase in the T1E (<7%) was observed. The inclusion of the additional cGMR did not change the highest inflation of the T1E. Finally, a significant sample size reduction was observed and the inclusion of the cGMR usually did not increase the required sample size

EMA commentary on the ICH guideline for testing for carcinogenicity of pharmaceuticals

The global regulatory requirements for the assessment of the carcinogenic potential of pharmaceuticals provided for the conduct of long-term carcinogenicity studies in two rodent species, usually the rat and the mouse. Given the their extensive use of animals as well as the costs of these studies, it is in keeping with the mission of International Council on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) to examine whether this practice requiring long-term carcinogenicity studies in two species could be reduced without compromising human safety