1. Pharmacologic profiles of investigational kisspeptin/metastin analogues, TAK-448 and TAK-683, in adult male rats in comparison to the GnRH analogue leuprolide
Hisanori Matsui, et al. Eur J Pharmacol. 2014 Jul 15;735:77-85. doi: 10.1016/j.ejphar.2014.03.058. Epub 2014 Apr 18.
Kisspeptin/metastin, a hypothalamic peptide, plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons, and we have shown that continuous subcutaneous administration of kisspeptin analogues suppresses plasma testosterone in male rats. This study examined pharmacologic profiles of investigational kisspeptin analogues, TAK-448 and TAK-683, in male rats. Both analogues showed high receptor-binding affinity and potent and full agonistic activity for rat KISS1R, which were comparable to natural peptide Kp-10. A daily subcutaneous injection of TAK-448 and TAK-683 (0.008-8μmol/kg) for consecutive 7 days initially induced an increase in plasma luteinizing hormone and testosterone levels; however, after day 7, plasma hormone levels and genital organ weights were reduced. Continuous subcutaneous administrations of TAK-448 (≥10pmol/h, ca. 0.7nmol/kg/day) and TAK-683 (≥30pmol/h, ca. 2.1nmol/kg/day) induced a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3-7 days. This profound testosterone-lowering effect was sustained throughout 4-week dosing periods. At those dose levels, the weights of the prostate and seminal vesicles were reduced to castrate levels. These suppressive effects of kisspeptin analogues were more rapid and profound than those induced by the GnRH agonist analogue leuprolide treatment. In addition, TAK-683 reduced plasma prostate specific antigen (PSA) in the JDCaP androgen-dependent prostate cancer rat model. Thus, chronic administration of kisspeptin analogues may hold promise as a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases such as prostate cancer. Further studies are warranted to elucidate clinical significance of TAK-448 and TAK-683.
2. Usefulness of pharmacokinetic/efficacy analysis of an investigational kisspeptin analog, TAK-448, in quantitatively evaluating anti-tumor growth effect in the rat VCaP androgen-sensitive prostate cancer model
Kaori Ishikawa, Akira Tanaka, Akifumi Kogame, Tatsuya Watanabe, Yoshihiko Tagawa, Hisanori Matsui Eur J Pharmacol. 2018 Jun 5;828:126-134. doi: 10.1016/j.ejphar.2018.03.032. Epub 2018 Mar 23.
TAK-448 is a kisspeptin analog with improved in vivo potency. In our previous studies in the rat JDCaP prostate cancer model, TAK-448 showed more rapid and profound reductions in plasma testosterone (T) and prostate-specific antigen (PSA, a biomarker of prostate tumor growth) levels than the gonadotropin releasing hormone (GnRH) analog leuprolide (TAP-144); however, its effects on tumor volume and subsequent tumor recurrence have not been elucidated fully. To overcome these challenges, we established the rat VCaP subcutaneous xenograft model replicating both the androgen-sensitive and castration-resistant phases of prostate cancer, and we performed pharmacokinetic/efficacy (PK/E) correlation analyses to compare the overall anti-tumor growth effects of TAK-448 to those of TAP-144. Our approach demonstrated TAK-448 had greater anti-tumor growth potential, including in the castration-resistant phase, than TAP-144 in this rat VCaP model. TAK-448 treatment was associated with a reduction in intra-tumoral dihydrotestosterone levels, which might explain its superior anti-tumor activity. Thus, our PK/E analysis was effective at providing new insights into the therapeutic efficacy of TAK-448 as a novel ADT agent in our rat VCaP model.
3. Evaluation of pharmacokinetics/pharmacodynamics and efficacy of one-month depots of TAK-448 and TAK-683, investigational kisspeptin analogs, in male rats and an androgen-dependent prostate cancer model
Akira Tanaka, Daisuke Nakata, Tsuneo Masaki, Masami Kusaka, Tatsuya Watanabe, Hisanori Matsui Eur J Pharmacol. 2018 Mar 5;822:138-146. doi: 10.1016/j.ejphar.2018.01.012.
TAK-448 and TAK-683 are kisspeptin agonist analogs with improved in vivo stability and activity. Previous studies showed that continuous subcutaneous administration of TAK-448 or TAK-683 caused rapid and profound reductions in plasma testosterone levels in various species, including male healthy volunteers, suggesting their therapeutic potential as anti-prostate cancer agents. For clinical drug development, one-month sustained-release depots of TAK-448 and TAK-683, TAK-448-SR(1M) and TAK-683-SR(1M), were designed to improve usability in clinical practice. In this study, the pharmacokinetics/pharmacodynamics (PK/PD) profiles of TAK-448-SR(1M) and TAK-683-SR(1M) were initially tested in male rats to ensure their eligibility as one-month depots. The therapeutic advantages of TAK-448-SR(1M) and TAK-683-SR(1M) over TAP-144-SR(1M) were then investigated in a JDCaP xenograft rat model. TAK-448-SR(1M) and TAK-683-SR(1M) maintained certain levels of plasma TAK-448 free form (TAK-448F) and plasma TAK-683 free form (TAK-683F) for at least 4 weeks, before clearance from the circulation. Accompanying their desirable PK profiles, TAK-448-SR(1M) and TAK-683-SR(1M) showed favorable PD responses as one-month depots and demonstrated better testosterone control than TAP-144-SR(1M). Both depots exerted rapid and profound suppression of plasma testosterone levels in male rats. These profound suppressive effects were maintained in dose-dependent manners, before recovery toward normal levels. In the JDCaP xenograft model, TAK-448-SR(1M) and TAK-683-SR(1M) both showed better prostate-specific antigen (PSA) control than TAP-144-SR(1M), although all treatment groups eventually experienced PSA recurrence and tumor regrowth. In conclusion, this study demonstrates that both TAK-448-SR(1M) and TAK-683-SR(1M) have desirable and better PK/PD profiles than TAP-144-SR(1M) in rats, which could potentially provide better clinical outcomes in androgen-dependent prostate cancer.
