Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog, TAK‐448, for its anti‐tumor efficacy in a rat xenograft model
| العنوان: | Pharmacokinetic and pharmacodynamic modeling of the metastin/kisspeptin analog, TAK‐448, for its anti‐tumor efficacy in a rat xenograft model |
|---|---|
| المؤلفون: | Kaori Ishikawa, Yuu Moriya, Yoshihiko Tagawa, Takahiro Kondo, Joost DeJongh, Satoru Asahi, Akifumi Kogame, Hisanori Matsui |
| المصدر: | Biopharmaceutics & Drug Disposition. 41:283-294 |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Time Factors, Antineoplastic Agents, Hormonal, medicine.drug_class, Pharmaceutical Science, Pharmacology, Models, Biological, 030226 pharmacology & pharmacy, Rats, Nude, 03 medical and health sciences, Prostate cancer, 0302 clinical medicine, Kisspeptin, Pharmacokinetics, In vivo, Prostate, Leuprorelin, Cell Line, Tumor, medicine, Animals, Humans, Pharmacology (medical), Testosterone, Cell Proliferation, Kisspeptins, Chemistry, Prostatic Neoplasms, General Medicine, medicine.disease, Androgen, Xenograft Model Antitumor Assays, Rats, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Leuprolide, medicine.drug |
| الوصف: | TAK-448 is the investigational metastin/kisspeptin analog, which is known to have an anti-tumor effect through suppression of androgen hormones (luteinizing hormone and testosterone) levels. This study developed pharmacokinetic-pharmacodynamic (PK/PD) models of TAK-448 and leuprorelin acetate (TAP-144) in a rat vertebral-cancer of the prostate (VCaP) androgen-sensitive prostate cancer xenograft model to quantitatively assess and compare the anti-tumor effects of both drugs. A potential contribution of the hormone-independent direct effects of TAK-448 to the tumor growth inhibition was also investigated in the in vivo rat xenograft model, because our in vitro experiments revealed that TAK-448 may also directly suppress VCaP cellular proliferation. The PK/PD model successfully described the time course of tumor growth inhibition after drug treatment as well as the development of resistance to the inhibition of androgen hormones, following drug treatment or castration. The EC50 of the hormone-dependent inhibitory effect of TAK-448 was much lower than that of TAP-144, and TAK-448 also has a faster onset of anti-tumor effect than TAP-144, demonstrating that TAK-448 has a stronger overall anti-tumor effect than TAP-144. In addition, model inference, by incorporating a hormone-independent inhibition pathway of TAK-448 into the PK-PD model, suggested that such a direct inhibition pathway for TAK-448 cannot be excluded, as also indicated by in vitro studies, but its EC50 would be approximately three orders of magnitude higher than that of the hormone-dependent pathway. This study helps to understand the potential and mechanism of TAK-448 as a prostate cancer treatment. |
| تدمد: | 1099-081X 0142-2782 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b34e1824c7965a379f8ace9fc12ea2aa https://doi.org/10.1002/bdd.2245 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....b34e1824c7965a379f8ace9fc12ea2aa |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1099081X 01422782 |
|---|