PKPD modelling of the relationship between testosterone and PSA in patients with prostate cancer during treatment with leuprorelin – What is the optimal testosterone level?
N. Snelder(1), H. Drenth(1), K. Bergmann(1), N. Wood(2), M. Hibberd(2), and G. Scott(2)
(1) LAP&P Consultants BV, Leiden, The Netherlands, (2) Takeda Development Centre Europe Ltd, London, United Kingdom
Objectives: The main goal in the treatment of prostate cancer with gonadotropin-releasing hormone (GnRH) agonists is to achieve and maintain testosterone concentrations below castration level. However, this level is based on available, and improving, measurement techniques, while a relationship between testosterone and clinical outcome, i.e. survival [1], is lacking. Prostate specific antigen (PSA) serum concentrations are used as a surrogate marker for disease control in clinical practice [2]. This investigation aimed to characterize, in a quantitative manner, the relationship between leuprorelin (a GnRH agonist), testosterone and PSA concentrations over time in order to aid identification of a target testosterone concentration which optimises the balance of the benefits of testosterone suppression whilst reducing the risks of futile oversupression.
Methods: Data from a single dose study to investigate the effect of leuprorelin in a 6 month depot formulation on testosterone and PSA in prostate cancer patients were analysed using a population pharmacokinetic-pharmacodynamic (PKPD) modelling approach. The developed model was qualified using external data from two clinical studies, in which the effect of different formulations of leuprorelin on PSA and/or testosterone was evaluated in healthy elderly male volunteers and in prostate cancer patients, respectively.
Results: The effect of leuprorelin on the relationship between testosterone and PSA was adequately characterized by the Romero model [3] with minor modifications, combined with a turnover model to describe the delay in response between testosterone and PSA. A model based on the assumption that PSA concentrations do not decrease anymore even when testosterone concentrations would go to zero resulted in a significantly better description of the data, than a model assuming that both PSA and testosterone concentrations could go to zero.
Conclusions: The model-based analysis suggests that reducing testosterone concentrations below 35 ng/dL does not result in a further decrease in PSA levels (>95% of the minimal PSA level is reached). More data is required to support this relationship in the lower testosterone and PSA range. Since the absolute minimal PSA concentration reached during treatment with GnRH agonists is largely determined by the PSA concentration before treatment, the percentage reduction in PSA may be a better criteria for response to treatment than the he absolute minimal PSA concentration.
References:
[1] Tombal B (2005). Appropriate castration with luteinising hormone releasing hormone (LHRH) agonists: what is the optimal level of testosterone? Eur Urol Suppl. 4:14–19.
[2] Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, Mason M, Matveev V, Wiegel T, Zattoni F, Mottet N; European Association of Urology (2014). EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014 Feb;65(2):467-79.
[3] Romero E, Vélez de Mendizabal N, Cendrós JM, Peraire C, Bascompta E, Obach R, Trocóniz IF (2012). Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer. J Pharmacol Exp Ther. 342(3):788-98.
