John A. McLane

Polymer-delivered subcutaneous leuprolide acetate formulations achieve and maintain castrate concentrations of testosterone in four open-label studies in patients with advanced prostate cancer.

To determine whether luteinising hormone‐releasing hormone (LHRH) agonist, ATRIGEL® polymer‐delivered, subcutaneous, leuprolide acetate (ADSC‐LA), formulations suppressed serum testosterone to concentrations of ≤20 ng/dL.

Pharmacokinetic and pharmacodynamic comparison of subcutaneous versus intramuscular leuprolide acetate formulations in male subjects

Background: The aim of this study was to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of two distinct formulations of leuprolide acetate (LA); subcutaneous (SC) injection and intramuscular (IM) injection. Methods: A total of 32 healthy men were randomized to receive a single 7.5 mg injection of SC-LA (n = 16) or IM-LA (n = 16) in this phase I, open-label, parallel-group study. PK was assessed via LA concentrations, and PD via serum luteinizing hormone (LH) and testosterone (T) concentrations. Results: The initial surge of LA was higher for IM-LA than SC-LA (Cmax 27 ± 4.9 versus 19 ± 8.0 ng/ml, respectively), with a shorter tmax (1.0 ± 0.4 versus 2.1 ± 0.8 h). The duration of quantifiable LA concentration was longer for SC-LA (up to 56 versus 42 days for SC-LA and IM-LA, respectively). Median LH concentrations in both groups rapidly increased, followed by gradual decrease. However, SC-LA demonstrated a longer duration of LH suppression, with median levels remaining below 1.0 IU/l through Day 56 compared with IM-LA where LH started to rise by Day 35. Consequently, serum T began to increase by Day 42 in the IM-LA group, with only four subjects maintaining levels ⩽50 ng/dl, compared with 14 subjects in the SC-LA group. By Day 56, 13 SC-LA subjects maintained serum T levels ⩽50 ng/dl. Both SC-LA and IM-LA were well tolerated. Conclusions: Both formulations demonstrated consistent delivery of drug over 1 month; however, SC-LA provided a longer duration of action than expected based on the dosing interval. This profile suggests that SC-LA will provide effective suppression of T over a longer period of time, permitting greater injection scheduling flexibility.

MP57-17 POLYMER DELIVERED, SUBCUTANEOUSLY ADMINISTERED LEUPROLIDE ACETATE PROVIDES STABLE AND LONG-TERM DRUG DELIVERY AND TESTOSTERONE SUPPRESSION ACROSS 4 PIVOTAL TRIALS

INTRODUCTION AND OBJECTIVES: The presence of metabolic syndrome in men with prostate cancer (PCa) undergoing androgen-deprivation therapy (ADT), especially intermittent type, has not been completely evaluated. The aim of this study is to evaluate metabolic syndrome in men with PCa undergoing intermittent ADT. METHODS: In this longitudinal study, we studied the prevalence of metabolic syndrome and its components in 190 patients who were undergoing intermittent ADT. The metabolic syndrome was defined according to the Adult Treatment Panel III criteria. All metabolic parameters, including lipid profile, blood glucose, blood pressures, and waist circumferences of the patients were measured six and 12 months after treatment. RESULTS: Mean age of the patients was 67.5 6.74 years. The incidence of metabolic syndrome after six and 12 months was 6.8% and 14.7%, respectively. Analysis of various components of the metabolic syndrome revealed that patients had significantly higher overall prevalence of hyperglycemia, abdominal obesity, and hypertriglyceridemia in their sixand 12-month follow ups, but blood pressure has not been changed in the same period except for diastolic blood pressure after six months. CONCLUSIONS: Although there was an increased risk of metabolic syndrome in patients receiving intermittent ADT, it was lower than other studies that treated the same patients with continuous ADT. Also it seems that intermittent ADT has less metabolic complications than continuous ADT and could be used as a safe alternative in patients with advanced and metastatic PCa.

Polymer delivered, subcutaneously administered leuprolide acetate provides stable and long-term drug delivery and testosterone suppression in 4 pivotal trials.

e592Background: Prostate cancer patients receive androgen deprivation therapy (ADT) to suppress testosterone (T) to prevent proliferation of cancer cells. T suppression levels achieved by bilateral orchiectomy remain the gold standard for the target of suppression by ADT. Although the historical threshold definition of castration is T ≤ 50 ng/dL, increasing evidence suggests T lower than 20ng/dL may improve clinical outcomes, e.g., an increased cancer specific survival and delayed disease progression. To determine the minimal threshold of serum leuprolide required to maintain castrate level T suppression in prostate cancer patients, data from 4 pivotal trials evaluating long-acting, subcutaneously (SC) administered leuprolide acetate (LA) formulated with a biodegradable polymer were pooled. Methods: 438 eugonadal prostate cancer patients (age 40-86) were treated with SC-LA at 7.5, 22.5, 30, or 45mg delivered with a single dose lasting over 1, 3, 4, or 6 months (n = 120, 117, 90, 111), respectively in 4 op...

MP73-16 SOLID DEPOT, CONTINUOUS RELEASE, SUBCUTANEOUS LEUPROLIDE ACETATE FORMULATIONS LASTING 1-6 MONTHS ACHIEVE AND MAINTAIN SERUM TESTOSTERONE LEVELS BELOW 20NG/DL IN 4 OPEN LABEL, FIXED DOSE STUDIES

INTRODUCTION AND OBJECTIVES: Increasing evidence suggests that lower serum testosterone (T) levels during androgen deprivation therapy (ADT) impact clinical outcomes in prostate cancer. Recent studies demonstrated increased overall survival and time to PSA progression free survival among patients who consistently attained castrate levels of T 20 ng/dL. While the US definition for effective castration has historically been T 50 ng/dL, the European Association of Urology guidelines have updated the target level to T 20 ng/dL. Hence, the objective of this analysis was to evaluate subcutaneous (SQ) Atrigel technology leuprolide acetate (LA) pivotal trial data in 1, 3, 4, and 6 month dose formulations to determine whether a SQ depot LHRH agonist suppressed T to achieve a more rigorous androgen suppression level of 20 ng/dL. METHODS: In 4 open label, fixed dose studies, male patients aged 40-86 years with prostate cancer, whom had not undergone ADT, were treated with a single SQ depot formulation of LA: 7.5 mg over 28 days, 22.5 mg over 3 months, 30 mg over 4 months, or 45 mg of drug over 6 months. Serum T was sampled at screening, baseline, 2, 4, 8 hours post-dosing, days 1, 2, 3, 7, and every week until the next dose, at which time, the sampling schedule repeated until the end of study (6 months for 1 and 3 month doses, 8 months for 4 month dose, and 12 months for 6 month dose). Descriptive statistics were used to summarize the concentrations at each time point as well as to determine time to T suppression. RESULTS: Mean serum T levels at end of study were consistently below 20 ng/dL for each trial (6.1 0.4, 10.1 0.7, 12.4 0.8, 12.6 2.1 for the 1 [N1⁄4117], 3 [N1⁄4111], 4 [N1⁄482], 6-month doses [N1⁄4103], respectively). During the 12-month trial of the 6 month formulation, a high proportion (94%) of study patients achieved serum T 20 ng/dL within 6 weeks after dosing. 92-96% of patients maintained serum T 20 ng/dL from week 6-24. CONCLUSIONS: All doses of SQ-LA rapidly achieved and maintained consistent mean serum T below the more rigorous 20 definition of castration. These data suggest that SQ-LA via Atrigel technology achieves a favorable lower level of T suppression, which may represent an important metric for improving survival and delaying progression in prostate cancer.