Pharmacokinetics and pharmacodynamics of abarelix, a gonadotropin-releasing hormone antagonist, after subcutaneous continuous infusion in patients with prostate cancer.

OBJECTIVES

Our objective was to evaluate the pharmacokinetic and pharmacodynamic characteristics of abarelix after continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1) in patients with prostate cancer and to identify a plasma concentration of abarelix that may provide a sustained pharmacodynamic effect.

METHODS

This was a multicenter, open-label trial to evaluate abarelix, administered as a continuous subcutaneous infusion for up to 84 days (12 weeks) in 36 men with clinically localized or regional prostate cancer. All patients were treated at a dosage of 50 microg x kg(-1) x d(-1) for at least 28 days (4 weeks). The pharmacokinetic characteristics and the pharmacologic activities of abarelix on testosterone, prostate-specific antigen, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone during and after treatment with abarelix were measured.

RESULTS

After a continuous subcutaneous infusion of 50 microg x kg(-1) x d(-1), abarelix concentrations peaked with the median observed time to reach peak concentration at approximately 28 days. The mean observed maximum plasma drug concentration and average plasma concentration were 56.1 and 48.6 ng/mL, respectively. The mean observed half-life of abarelix was 10.0 days. Mean testosterone, dihydrotestosterone, follicle-stimulating hormone, and luteinizing hormone inhibition of 94.2%, 88.7%, 79.7%, and 82.8%, respectively, were achieved by study day 15 (14 days after dosing started), and inhibition continued to be maintained until the last dosing day. For the prostate-specific antigen levels, mean inhibition of 52.5% was achieved by 28 days after dosing started. The inhibition progressively increased and peaked at 81.9% on the final day of dosing. The inhibition for prostate-specific antigen was extended to 94.6% during the final follow-up visit (28 to 35 days after treatment ended). The median prostate gland volume reduction at treatment exit was 35%. The population pharmacodynamic estimates (percent coefficient of variation) of the 50% inhibitory concentration, maximum organ extraction ratio, and slope and sigmoidicity of the effect-concentration curve of abarelix to testosterone were 3.47 ng/mL (12.4%), 94.9 (1.3%), and 2.92 (16.2%), respectively.

CONCLUSIONS

The results show that abarelix given as a subcutaneous infusion of 50 microg x kg(-1) x d(-1) is sufficient to produce clinically significant effects on the basis of prostate gland volume reduction and the suppression of gonadotropins.