Aims
This investigation aimed to quantitatively characterize the relationship between the gonadotropin‐releasing hormone (GnRH) agonist leuprorelin, testosterone (T) and Prostate specific antigen (PSA) concentrations over time, to aid identification of a target T concentration which optimises the balance of the benefits of T suppression whilst reducing the risk of side effects related to futile over‐suppression.
Methods
Data from a single dose study to investigate the effect of leuprorelin in a 6‐month depot formulation on T 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 three studies, in which the effect of different formulations of leuprorelin on T and PSA was evaluated in prostate cancer patients.
Results
The effect of leuprorelin on the relationship between T and PSA was adequately characterized by the Romero model with minor modifications, combined with a turnover model to describe the delay in response between T and PSA. The data was significantly better described when assuming a minimum PSA level which is independent on the treatment related reduction in T, as compared to a model with a proportional reduction in PSA and T.
Conclusions
The model‐based analysis suggests that on a population level, reducing T 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 T and PSA range.
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