A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy

Abstract

Intermittent androgen deprivation therapy with gonadotropin-releasing-hormone (GnRH) agonists can prevent or delay disease progression and development of castration resistant prostate cancer for subpopulations of prostate cancer patients. It may also reduce risk and severity of side effects associated with chemical castration in prostate cancer (PCa) patients. One of the earliest comprehensively documented clinical trials on this was reported in a Canadian patient population treated with leuprorelin preceded by a lead-in with cyproterone acetate. A systems-based mixed effect analysis of testosterone response in active and recovery phases allows inference of new information from this patient population. Efficacy of androgen deprivation therapy is presumed to depend on a treshold value for testosterone at the nadir, below which no additional beneficial effects on PSA reponse can be expected, and occurance of testosterone breakthroughs during active therapy. The present analysis results in a mixed effect model, incorporating GnRH receptor activation, testosterone turnover and feedback mechanisms, describing and predicting testosterone inhibition under intermittent androgen deprivation therapy on the individual and population level, during multiple years of therapy. Testosterone levels in these patients decline over time with an estimated first order rate constant of 0.083 year−1(T1/2 = 8.4 y), with a substantial distribution among this patient population, compared to the general population. PCa patients leaving the trial due to unmanageble PSA relapse appear to have slightly higher testosterone levels at the nadir than sustained responders. These findings are expected to contribute to an increased understanding of the role of testosterone in long term disease progression of prostate cancer.

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All authors contributed to the model analysis results. The first draft of the manuscript was written by JD and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Joost DeJongh.

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Nelleke Snelder, Maurice Ahsman and Joost DeJongh were paid consultants for Takeda Development Centre Europe Ltd. before the conduct of the analysis.

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DeJongh, J., Ahsman, M. & Snelder, N. A population K-PD model analysis of long-term testosterone inhibition in prostate cancer patients undergoing intermittent androgen deprivation therapy. J Pharmacokinet Pharmacodyn (2021). https://doi.org/10.1007/s10928-020-09736-7

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Keywords

  • Testosterone
  • Testosterone decline rate
  • Population K-PD model
  • PSA
  • Prostate cancer
  • Leuprorelin
  • iADT