Evaluation of the pharmacokinetics and pharmacodynamics of two leuprolide acetate 45 mg 6-month depot formulations in patients with prostate cancer.

The pharmacokinetics (PK) and pharmacodynamics of two leuprolide acetate (LA) 45 mg 6-month depot formulations were characterized in prostate cancer patients. Subjects (planned N = 150 in each cohort) received two intramuscular injections of LA Formulation-A or Formulation-B administered 24 weeks apart. Samples were collected for the measurement of testosterone, LH (all subjects) and leuprolide (in a subset of subjects approximately N = 24 in each cohort) at the same time points. Leuprolide PK profile showed an initial peak followed by a rapid decline over the first week post-dose, with mean leuprolide concentrations staying relatively constant through the end of 24-week period. Mean testosterone and LH serum concentrations showed initial increases above baseline values after the first dose and then decreased to 16.0 ng/dL and 0.6 mIU/mL by Week 4 for Formulation-A and were maintained at ≤14.3 ng/dL and 0.4 mIU/mL, thereafter, with negligible mean increases after the second dose. Formulation-A showed a lower initial peak and higher leuprolide concentration during the sustained release phase which may explain higher testosterone suppression rates for Formulation-A compared to Formulation-B. Differences in PK between LA depot formulations were reflected in pharmacodynamic responses, with a higher rate of testosterone suppression and less escapes and acute-on-chronic responses for Formulation-A.