CLINICAL PHARMACOLOGY
Leuprolide acetate, an LH-RH agonist, acts as a potent inhibitor of gonadotropin secretion when given continuously and in therapeutic doses. Animal and human studies indicate that after an initial stimulation, chronic administration of leuprolide acetate results in suppression of ovarian and testicular steroidogenesis.
In humans, administration of leuprolide acetate results in an initial increase in circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), leading to a transient increase in concentrations of gonadal steroids (testosterone and dihydrotestosterone in males, and estrone and estradiol in premenopausal females). However, continuous administration of leuprolide acetate results in decreased levels of LH and FSH. In males, testosterone is reduced to castrate levels. These decreases occur within 2 to 4 weeks after initiation of treatment.
One Viadur® Implant nominally delivers 120 micrograms of leuprolide acetate per day over 12 months. Leuprolide acetate is not active when given orally.
PHARMACOKINETICS
Absorption: After insertion of Viadur®, mean serum leuprolide concentrations were 16.9 ng/mL at 4 hours and 2.4 ng/mL at 24 hours. Thereafter, leuprolide was released at a constant rate. Mean serum leuprolide concentrations were maintained at 0.9 ng/mL (0.3 to 3.1 ng/mL; SD = ±0.4) for 12 months. Upon removal and insertion of a new Viadur® at 12 months, steady-state serum leuprolide concentrations were maintained. Distribution: The mean steady-state volume of distribution of leuprolide following 1 mg intravenous (IV) bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%. 1 Metabolism: In healthy male volunteers administered a 1 mg IV bolus of leuprolide, the mean systemic clearance was 8.34 L/h, with a terminal elimination half-life of approximately 3 hours, based on a two-compartment model.1
A pentapeptide (M-1) is the major leuprolide metabolite upon administration with different leuprolide acetate formulations. No drug metabolism study was conducted with Viadur®. Excretion: No drug excretion study was conducted with Viadur®. Dose Proportionality: In a study comparing one Viadur® implant to two Viadur® implants, mean serum leuprolide concentrations were proportional to dose.
SPECIAL POPULATIONS:
Geriatrics: The majority (88%) of the 131 patients studied in clinical trials were age 65 and over. Pediatrics: The safety and effectiveness of Viadur® in pediatric patients have not been established (see CONTRAINDICATIONS).
Race: In the patients studied (80 Caucasian, 23 Black, 3 Hispanic), mean serum leuprolide concentrations were similar. Renal and Hepatic Insufficiency: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined. Drug-Drug Interactions: No pharmacokinetic drug-drug interaction studies were conducted with Viadur®.
CLINICAL STUDIES
In two open-label, non-comparative, multicenter studies, 131 patients with prostatic cancer were treated with Viadur® and evaluated for up to two years. Two-thirds of the patients had stage C or less advanced disease. The dose-ranging study assessed serum testosterone as the primary efficacy endpoint in 51 patients treated with either one [n=27] or two [n=24] implants for 12 months. The confirmatory study evaluated achievement and maintenance of serum testosterone suppression in 80 patients each treated with one implant for 12 months. Both studies included a removal procedure and insertion of a new implant with evaluation for 12 additional months.
Following the initial insertion in patients receiving one implant, mean serum testosterone concentrations increased from 422 ng/dL at baseline to 690 ng/dL on Day 3, then decreased to below baseline by week two (Figure B). Serum testosterone decreased below the 50 ng/dL castrate threshold by week four in all but one patient [106 of 107 patients, 99%]. Once serum testosterone suppression was achieved [one patient was not continuously suppressed until week 28], testosterone remained suppressed below the castrate threshold for the duration of the treatment phase.
Most patients [n=118] had a new implant inserted for a second year of therapy following removal of the first implant(s). No patient experienced a clinically significant increase in serum testosterone [acute-on-chronic phenomenon] upon removal of the original implant(s) and insertion of a new implant. Suppression of serum testosterone was maintained in all patients through the two-month follow-up period following removal of the first implant(s) and insertion of a new implant.
Serum Prostate Specific Antigen (PSA) was monitored as a secondary endpoint in the clinical studies with Viadur®. Serum PSA decreased in all patients after they began treatment with Viadur®. At six months, PSA concentrations decreased from baseline by at least 90% in 74.2% of the 97 evaluable patients.
Periodic monitoring of serum testosterone and PSA concentrations is recommended, especially if the anticipated clinical or biochemical response to treatment has not been achieved.
|
