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

• Published in: European journal of pharmacology 2018-06, Vol.828, p.126-134
• Main Authors: Ishikawa, Kaori, Tanaka, Akira, Kogame, Akifumi, Watanabe, Tatsuya, Tagawa, Yoshihiko, Matsui, Hisanori
• Format: Article
• Language: English
• Subjects: Androgen-deprivation therapy (ADT); Kisspeptin; Leuprolide (TAP-144); PK/efficacy modeling; Prostate cancer; TAK-448
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2018.03.032

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.