title: Evaluation of the pharmacokinetics and pharmacodynamics of two leuprolide acetate 45 mg 6-month depot formulations in patients with prostate cancer.
abstract: 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.
authors.affiliation: Pharmaceutical Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Nael M
authors.initials: NM
authors.lastname: Mostafa
authors.affiliation: Pharmaceutical Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Kristof
authors.initials: K
authors.lastname: Chwalisz
authors.affiliation: Pharmaceutical Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Lois
authors.initials: L
authors.lastname: Larsen
authors.affiliation: Pharmaceutical Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Mattia-Goldberg
authors.affiliation: South Orange County Medical Research Center, Laguna Hills, CA, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Spitz
authors.affiliation: Pharmaceutical Development, AbbVie Inc., North Chicago, IL, USA.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Pradhan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D003692:Delayed-Action Preparations; D004339:Drug Compounding; D006801:Humans; D007273:Injections, Intramuscular; D016729:Leuprolide / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome; D014481:United States
chemical_list: D018931:Antineoplastic Agents, Hormonal; D003692:Delayed-Action Preparations; D013739:Testosterone; D007986:Luteinizing Hormone; D016729:Leuprolide
keywords: GnRH agonist; leuprolide; pharmacodynamics; pharmacokinetics