Preclinical pharmacokinetics and metabolism study of SCO-267, a GPR40 full agonist, in beagle dogs using ultra-high performance liquid chromatography coupled to tandem mass spectrometry.

SCO-267 is a GPR40 full agonist that has been developed for the treatment of diabetes. To support its preclinical and clinical development, in this study, we developed an ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of SCO-267 in dog plasma using cabozantinib as internal standard (IS). The chromatographic separation was obtained on a Waters acquity BEH C18 column (50 × 2.1 mm, i.d., 1.7 µm) and the detection was performed using Thermo TSQ triple quadrupole mass spectrometer with multiple reaction monitoring positive mode at m/z 615.3 > 230.1 for SCO-267 and m/z 502.5 > 323.3 for IS. The method was validated over the concentration range of 1-2,000 ng/ml with the lower limit of quantification of 1 ng/ml. The selectivity, linearity, precision and accuracy over this range were acceptable. The extraction recovery was more than 88.73% and no matrix effect was observed. SCO-267 was demonstrated to be stable during the storage and processing period. The new method was successfully applied to the pharmacokinetic study in beagle dogs following a single oral and intravenous administration. The oral bioavailability was 64.34%. In addition, the metabolites from dog liver microsomal incubation and plasma collected after an oral administration were identified by a UHPLC-HRMS method. The biotransformation pathways of SCO-267 involved oxygenation, O-demethylation, N-dealkylation and acyl glucuronidation.

Development and Comparison of Intramuscularly Injected Long-acting Testosterone Undecanoate Nano-/Microcrystal Suspensions with Three Different Particle Size.

The aim of this study was to develop and compare the pharmacokinetic property of testosterone undecanoate (TU) nano-/microcrystal suspension with three different particle sizes after intramuscular (i.m.) administration. TU nano-/microcrystal suspensions were prepared by high pressure homogenization method and the mean particle size was 0.30 ± 0.11 µm (A), 1.21 ± 0.37 µm (B), and 4.83 ± 0.60 µm (C), respectively. Scanning electron microscope (SEM) was employed to observe the morphology of nano-/microcrystal suspensions after operation. X-ray Powder diffraction (XRPD) confirmed the crystalline state of TU in nano-/microcrystal suspension. After storage at 4 °C and 25 °C under mechanical shaking for 2 months, physical and chemical stabilities of nano-/microcrystal suspensions were measured by particle size analyzer and high performance liquid chromatography. There was no obvious change in particle size distribution and content of TU. After i.m. administration of suspension C to rats, the concentration of TU in plasma lasted for nearly 12 days that was comparative with the commercial testosterone undecanoate injection. The results showed that microcrystal C with a larger particle size had long-acting effect comparing with other two suspensions. The muscle irritation test in rabbits showed that the local irritation of TU nano-/microcrystal suspensions was lower than that of commercial testosterone undecanoate injection. It can be concluded that appropriate particle size of nano-/microcrystal suspensions for i.m. administration of TU was important to achieve better therapeutic effect.

Outcome Prediction and Evaluation by Imaging the Key Elements of Therapeutic Responses to Cancer Immunotherapies Using PET.

Cancer immunotherapy (also known as immuno-oncology), a promising anti-cancer strategy by harnessing the body's own immune system against cancer, has emerged as the "fifth therapeutic pilla" in the field of cancer treatment since surgery, chemotherapy, radiation and targeted therapy. Clinical efficacy of several immunotherapies has been demonstrated in clinical settings, however, only a small subset of patients exhibit dramatic or durable responses, with the highest reported frequency about 10-40% from single-agent PD-L1/PD-1 inhibitors, suggesting the urgent need of consistent objective response biomarkers for monitoring therapeutic response accurately, predicting therapeutic efficacy and selecting responders. Key elements of therapeutic responses to cancer immunotherapies contain the cancer cell response and the alternation of inherent immunological characteristics. Here, we document the literature regarding imaging the key elements of therapeutic responses to cancer immunotherapies using PET. We discussed PET imaging approaches according to different response mechanisms underlying diverse immune-therapeutic categories, and also highlight the ongoing efforts to identify novel immunotherapeutic PET imaging biomarkers. In this article, we show that PET imaging of the key elements of therapeutic responses to cancer immunotherapies using PET can allow for more precise prediction, earlier therapy response monitoring, and improved management. However, all of these strategies need more preclinical study and clinical validation before further development as imaging indicators of the immune response.