6-month Depot Formulation Research Articles

7128 Efficacy and Safety of Leuprolide Acetate 3M Depot in Chinese Children with Central Precocious Puberty: Interim Analysis of Multicenter, Single-Arm, Prospective Study

Abstract Disclosure: X. Luo: Advisory Board Member; Self; Takeda. L. Hou: Advisory Board Member; Self; Takeda. Y. Li: Advisory Board Member; Self; Takeda. Y. Sun: Advisory Board Member; Self; Takeda. X.K. Jin: Employee; Self; Takeda. Background: Central precocious puberty (CPP) due to early activation of the hypothalamic-pituitary-gonadal axis leads to early puberty. CPP has a negative impact on adult height. Leuprolide acetate (LA), a gonadotropin-releasing hormone agonist (GnRHa) is the standard treatment for CPP. As CPP requires prolonged treatment, a 3-month (3M) depot formulation would increase patient compliance and reduce the injection burden. This interim analysis presents the effect of LA 3M depot on the gonadotropic axis and assesses safety in children with CPP. Methods: In this open-label, multicenter, single-arm, and prospective study, 31 children with CPP were included. Key inclusion criteria were the appearance of secondary sexual characteristics below the age of eight years in girls and nine years in boys with a confirmed diagnosis of CPP. Children treated with prior GnRHa and/or having underlying medical conditions were excluded. Eligible children were treated with LA 11.25 mg subcutaneously every 12 weeks. The primary endpoint of this interim analysis was the proportion of children achieving inhibition of peak LH defined as peak LH ≤ 3.0 IU/L in the GnRH stimulation test at weeks 24. The secondary endpoint was safety analysis in the children receiving at least one dose of LA 3M depot. Results: At baseline, 30 girls and one boy were enrolled. The median (95% CI) chronological age (CA) of the girls was 8.0 (7.0, 9.0) years and the boy was 10 years old. Girls had a median height of 136.95 (131.5, 139.7) cm, weight of 30 (27, 34) kg, and BMI of 16.4 (15.1, 17.9) kg/m2. Baseline bone (BA) age was 11 (10, 11) years, and BA/CA was 1.24 (1.2, 1.3). Boy’s characteristics at baseline differed in CA (10 years), height (144 cm), and BMI (17.4 kg/m2) from girls of this cohort. Due to the data collection time points for the interim analysis, 8 out of the 31 enrolled subjects had a visit at week 24, and 30 subjects reached the week 12 visit time point and had a visit at week 12. The percentage of children achieving inhibition of peak LH (≤ 3.0 IU/L) in the GnRH stimulation test at week 12 was 100 (88.4, 100) %. At week 24, all of them achieved inhibition of LH in the GnRH stimulation test 100 (63, 100) %. Decreases in BA/CA from baseline at weeks 12 and 24 are 93 (77.9, 99.2) % and 50 (15.7, 84.3) % respectively. No progression of the Tanner stage was observed in 96.7 (82.8, 99.9) % and 100 (63, 100) % at weeks 12 and 24. At the data cut-off, 4 (13.33%) patients experienced a total of 5 treatment-emergent adverse events (TEAEs) in the safety population of 30 subjects. No grade ≥3 AE or serious AE was reported. The incidence of injection site reaction was 3.33%. Conclusion: LA at 11.25mg/3M depot effectively suppresses the gonadotropic axis at weeks 12 and 24, normalizing growth and reversibly slowing the early onset of puberty in children with CPP. LA in a 3-month injecting frequency is a safe and convenient treatment option to improve patient compliance. Presentation: 6/3/2024

Population pharmacokinetic–pharmacodynamic modelling of the relationship between testosterone and prostate specific antigen in patients with prostate cancer during treatment with leuprorelin

This investigation aimed to quantitatively characterize the relationship between the gonadotropin-releasing hormone agonist leuprorelin, testosterone (T) and prostate specific antigen (PSA) concentrations over time, to aid identification of a target T concentration that optimises the balance of the benefits of T suppression whilst reducing the risk of side effects related to futile over-suppression. Data from a single dose study to investigate the effect of leuprorelin in a 6-month depot formulation on T and PSA in prostate cancer patients were analysed using a population pharmacokinetic-pharmacodynamic modelling approach. The developed model was qualified using external data from 3 studies, in which the effect of different formulations of leuprorelin on T and PSA was evaluated in prostate cancer patients. The effect of leuprorelin on the relationship between T and PSA was adequately characterized by the Romero model with minor modifications, combined with a turnover model to describe the delay in response between T and PSA. The data were significantly better described when assuming a minimum PSA level that is independent on the treatment-related reduction in T, as compared to a model with a proportional reduction in PSA and T. The model-based analysis suggests that on a population level, reducing T concentrations below 35ng/dL does not result in a further decrease in PSA levels (>95% of the minimal PSA level is reached). More data are required to support this relationship in the lower T and PSA range.

A New Sustained-release, 3-Month Leuprolide Acetate Formulation Achieves and Maintains Castrate Concentrations of Testosterone in Patients With Prostate Cancer

PurposeThis clinical trial investigated the effectiveness, pharmacokinetic properties, and safety profile of leuprolide acetate 22.5-mg depot, a new 3-month leuprolide depot formulation, as androgen deprivation therapy for patients with prostate cancer. MethodsA Phase III, open-label, multicenter study design for patients with prostate cancer, with patient inclusion assessed by the investigative site as patient's appropriate for androgen deprivation therapy. Patients received 2 separate intramuscular injections of leuprolide acetate 22.5-mg depot for a 3-month depot interval of therapeutic effect. Plasma testosterone concentrations were determined throughout the study. The primary efficacy analysis was the percentage of patients who achieve and maintain castrate testosterone levels (≤50 ng/mL) from days 28–168. Secondary end points included luteinizing hormone, follicle-stimulating hormone, prostate-specific antigen, and safety assessments. A pharmacokinetic study was also conducted in a subset of 30 patients. FindingsAll 163 patients enrolled in the study received at least 1 dose of study drug; 162 of them were fully evaluable and 151 completed the study. Castrate levels of testosterone were achieved and maintained from days 28–168 in 96.8% (95% CI, 92.5%–98.7%) of patients. Five patients presented with sporadic testosterone levels >50 ng/dL. By day 28, of the 161 patients, 150 (99.4%) had achieved castrate levels, and 127 (78.9%) had achieved testosterone concentrations ≤20 ng/dL. At study end, 149 of 151 patients (98.7%) patients achieved castrate testosterone levels, with 142 of 151 (94.0%) having testosterone levels ≤20 ng/dL. At study end, mean luteinizing hormone and follicle-stimulating hormone concentrations had decreased from baseline to below the lower limit of quantitation and below baseline levels, respectively, whereas mean serum prostate-specific antigen was reduced by 94.7% from baseline. Most patients (>96%) had no change in their World Health Organization/Eastern Cooperative Oncology Group score, whereby 84.0% of patients had a baseline score of 0. Bone pain, urinary pain, and urinary symptoms were infrequent and remained so throughout the study. After administration, leuprolide concentrations increased rapidly. The peak was followed by a decline up to day 28, maintaining sustained drug levels until the following dose on day 84. The most common related treatment-emergent adverse events, detected in >5% of patients, were hot flushes, fatigue, and injection site pain reported by 77.3%, 9.8%, and 9.2% of patients, respectively. ImplicationsLeuprolide acetate 22.5-mg depot was effective in achieving and maintaining testosterone suppression. Safety and tolerability profiles were consistent with established profiles of androgen deprivation therapy. Clinical Trials.gov identifier: NCT01415960.

Efficacy and Tolerability of Leuprorelin Acetate (Eligard®) in Daily Practice in Germany: Pooled Data from 2 Prospective, Non-Interventional Studies with 3- or 6-Month Depot Formulations in Patients with Advanced Prostate Cancer

Introduction: We evaluated the efficacy and tolerability of 3- and 6-month leuprorelin acetate (LA) depot formulations (Eligard®, Astellas Pharma GmbH) in patients with advanced prostate cancer treated in routine clinical practice in Germany. Materials and Methods: Data was pooled from 2 prospective, open-label, non-interventional studies in which 1,906 patients were treated for 12 months with either the 3-month (n = 633) or 6-month (n = 1,273) LA formulation. Results: Median prostate-specific antigen levels in the pooled patient population declined from 12.0 ng/mL at baseline to 0.5 ng/mL after 12 months. Prostate-specific antigen reduction was achieved in treatment-naïve and pre-treated patients. Adverse events were documented in 8.8% of patients. Conclusions: These pooled data from routine clinical practice in Germany indicate that LA 3- and 6-month depot injections can effectively reduce prostate-specific antigen levels in a broad patient population with advanced prostate cancer.

Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations

Aims: This study aimed to evaluate the economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot from a societal perspective in Japanese prostate cancer patients.Methods: The cost analysis estimated the reduction in direct and indirect costs as well as intangible costs saved by having one less injection. Claims data were used for the analyses of direct and indirect costs reduction. A discrete choice experiment based on a web-based survey estimated the monetary value of the intangible costs for one injection. Another web-based survey of prostate cancer patients, who had received treatment with leuprorelin acetate injections, was carried out to calibrate the results of the discrete choice experiment.Results: Reductions in medical costs and loss of productivity for having one less injection in prostate cancer patients receiving leuprorelin acetate were JPY 5,670 and JPY 1,723, respectively. Intangible costs saved by using a 6-month depot formulation instead of a 3-month depot formulation for the injection of leuprorelin acetate were estimated to be JPY 19,872, including the values for a reduction in pain (JPY 3,131), injection site reactions (JPY 11,545), waiting time (JPY 9,479), and subtracting the value of medical consultation (JPY 4,283). The total cost reduction for having one less injection was JPY 27,265.Limitations: The respondents from the internet panel provided by a survey company are not necessarily a representative population of Japanese society.Conclusions: Leuprorelin acetate 6-month depot has an advantage in monetary value in the reduction in medical costs, loss of productivity, and intangible costs for having one less injection in prostate cancer patients compared with leuprorelin acetate 3-month depot. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.

Cost analysis of leuprorelin acetate in Japanese pre-menopausal breast-cancer patients: comparison between 6-month and 3-month depot formulations

Aims: The aim in this study is to evaluate economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot in Japanese pre-menopausal breast cancer patients from a societal perspective.Methods: The cost analysis was conducted by estimating direct and indirect cost, and intangible costs associated with one 6-month injection compared with two 3-month injections. Claims data were used for the analyses of direct and indirect cost and Medical Fee Schedule Table for direct cost. Discrete choice experiments were conducted by web-based survey to determine the intangible costs. Another web-based survey was also conducted on premenopausal breast cancer patients with injections of leuprorelin acetate, to calibrate the results of discrete choice experiments.Results: The medical costs saved for having one less injection in pre-menopausal breast cancer patients with leuprorelin acetate injection were JPY 6,183. The productivity loss saving was JPY 1,419. An estimation of intangible costs saved for having one less injection of leuprorelin acetate was JPY 58,430, which included the disbenefit due to pain (JPY 8,535), injection site reactions (JPY 44,051), waiting time (JPY 9,595), and subtracting value in medical consultation (JPY 3,751). The total cost saved for having one less injection was JPY 66,032.Limitations: The respondents from the internet panel provided by a survey company do not necessarily reflect a population of Japanese society.Conclusions: Leuprorelin acetate 6-month depot demonstrates a higher value than leuprorelin acetate 3-month depot through saving medical costs and loss of productivity, as well as intangible costs saved for having one less injection when treating pre-menopausal breast cancer patients. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.

Final results of the prospective multicenter observational program RU-EGD-NI-001 for evaluation of efficacy and tolerability of the 6-month depot Eligard 45 mg in patients with advanced prostate carcinoma in routine clinical practice of uro-oncologists in the Russian Federation

Introduction . The 6-month depot formulation of leuproreline acetate 45 mg (Eligard, Astellas Pharma) was shown to reduce the levels of prostate-specific antigen (PSA) and testosterone and to be well tolerated in patients with advanced prostate cancer (PCa) in clinical trials as well as other depot formulations of leuproreline acetate (1- and 3-month). However, clinical trials are limited by strict patient inclusion and exclusion criteria. Objective of this study, sponsored by Astellas Pharma Russia, was to assess whether the efficacy and tolerability of the 6-month leuprorelin depot formulation could be confirmed in a broad and heterogeneous patient population encountered in daily clinical practice in the Russian Federation. Materials and methods . A non-interventional multicenter study (a observational program) was conducted in male patients with advanced PCa (T3–4, N+/M+, or with progression after local treatment) to whom Eligard 45 mg had been prescribed. Patients were followed every 6 months up to 24 months of treatment. Fifty three uro-oncologists from out-patient clinics in the Russia participated in the study. Results. The study enrolled 640 patients, of which 524 met inclusion/exclusion criteria. Mean age of the patients was 69.0 ± 8.6 years old (from 46 to 96 years old). In most cases hormonal therapy with Eligard 45 mg was performed for locally advanced PCa (50 % of patients), distant metastases were detected in 15 % subjects only, nodal involvement was detected in 12 % patients. Patients with initially localized prostate cancer (41.4 %) were prescribed Eligard 45 mg because of progression of their disease after local treatment or inability to receive any other treatment. Eligard 45 mg monotherapy was used in 92.75 % cases. Only 7.25 % patients received combined hormonal therapy with Eligard 45 mg and bicalutamide, flutamide and zoledronic acid. Mean serum PSA level was reduced by 81,7 % from 38,47 ng/ml at baseline to 7.05 ng/ml after 24 months of treatment, while mean testosterone level was reduced by 88 % from 92.12 to 11.03 ng/dl. Testosterone level below 50 and 20 ng/dl was reached by 97 and 88 % of patients. There was a change in mean quality of life based on EQ-5D-5L questionnaire: mean value of health status according to visual scale increased from 76.15 ± 14.10 to 78.22 ± 15.99 mm. The number of adverse drug reactions was low and amounted to 1.41 % of all patient population. Asthenia, headache, arterial hypertension, dizziness and nausea were the most commonly reported adverse drug reactions. Conclusions. These results suggest that the 6-month leuprorelin acetate depot formulations are well tolerated and reliably lower serum PSA and testosterone levels in daily clinical practice in patients with advanced PCa. These data are consistent with efficacy and tolerability results from clinical trials.

Comparative in vitro release and clinical pharmacokinetics of leuprolide from Luphere 3M Depot, a 3-month release formulation of leuprolide acetate

A 3-month depot formulation of leuprolide acetate (Luphere 3M Depot) with a mean microsphere diameter of 22.3 μm was prepared aseptically by spray-drying glacial acetic acid solution of the drug and polylactic acid, and lyophilization in a d-mannitol solution. The encapsulation efficiency and loading content of the drug in the Luphere 3M Depot were 94.7% and 9.92% (w/w), respectively. The in vitro release of leuprolide from the depot was substantially delayed and the release profile was similar to that of Lucrin Depot (Abbott Korea, Korea). The safety and pharmacokinetics of leuprolide were investigated over a period of 42 days in 20 prostate cancer patients following a subcutaneous injection of Luphere 3M or Lucrin Depot suspensions (leuprolide acetate dose of 11.25 mg) in a multi-center, randomized, single dose, parallel study. Both formulations were well tolerated by the patients and no serious adverse effects were observed during and after the study. No significant differences were observed in the maximum serum concentration (Cmax) and area under the curve (AUClast) of leuprolide between the two formulations. The results suggest comparable safety and efficacy profiles of Luphere 3M Depot and Lucrin Depot in clinical situations.

Efficacy and safety of leuprorelin acetate 6-month depot, TAP-144-SR (6M), in combination with tamoxifen in postoperative, premenopausal patients with hormone receptor-positive breast cancer: a phase III, randomized, open-label, parallel-group comparative study

BackgroundLeuprorelin acetate, a luteinizing hormone-releasing hormone agonist, is used worldwide in premenopausal women with hormone receptor-positive breast cancer. This study was conducted to assess the non-inferiority of the 6-month depot formulation, TAP-144-SR (6M) 22.5 mg to the 3-month depot formulation, TAP-144-SR (3M) 11.25 mg in postoperative, premenopausal patients with hormone receptor-positive breast cancer.MethodsThis was a 96-week phase III, randomized, open-label, parallel-group comparative study. All patients concomitantly received oral tamoxifen (20 mg daily). The primary endpoint was the suppression rate of serum estradiol (E2) to the menopausal level (≤30 pg/mL) from Week 4 through Week 48.ResultsIn total, 167 patients were randomized to receive TAP-144-SR (6M) (n = 83) or TAP-144-SR (3M) (n = 84) and the E2 suppression rate was 97.6 and 96.4 %, respectively. The estimated between-group difference was 1.2 % (95 % confidence interval −5.2 to 7.8). The non-inferiority of TAP-144-SR (6M) to TAP-144-SR (3M) for E2 suppression was confirmed. As for safety, common adverse events were hot flush and injection site reactions including induration, pain, and erythema in both treatment groups, which were of ≤Grade 2 in severity and not serious. No significant between-group differences in safety profiles and tolerability were observed.ConclusionsTAP-144-SR (6M) was not inferior to TAP-144-SR (3M) for its suppressive effect on serum E2. TAP-144-SR (6M) was also as well tolerated as TAP-144-SR (3M).

Abstract P5-12-07: Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer

Abstract Background: Luteinizing hormone-releasing hormone agonist + tamoxifen is standard postoperative adjuvant endocrine therapy for premenopausal patients with hormone receptor-positive breast cancer. Postoperative adjuvant endocrine therapy is now used for a longer period, and the longer-lasting leuprorelin acetate 6-month depot formulation (TAP-144-SR[6M]) is expected to increase patients' quality of life and decrease medical practitioners' burden. Methods: The hormone dynamics, pharmacokinetics (PK), safety, and efficacy of TAP-144-SR(6M) were compared with those of the 3-month depot formulation (TAP-144-SR[3M]) in a 96-week, phase 3 open-label parallel-group comparison study in premenopausal breast cancer patients after surgery (ClinicalTrial.gov ID: NCT01546649). Inclusion criteria were estrogen receptor (ER) and/or progesterone receptor (PgR) positive; TNM classification of T1-T3, any N, M0; and premenopausal (menstruation confirmed within the previous 12 weeks or both follicle-stimulating hormone [FSH] <40 mIU/mL and estradiol [E2] ≥10 pg/mL at enrollment). Patients were randomized to TAP-144-SR(6M) (6M group [6MG]) or TAP-144-SR(3M) (3M group [3MG]) based on number of axillary lymph node metastases, tumor size, age, ER/PgR status, chemotherapy or not, and study site. The primary endpoint was serum E2 suppression rate based on the menopausal level (≤30 pg/mL) from 4 to 48 weeks after the first administration. Secondary endpoints were serum hormone dynamics, efficacy (disease-free survival [DFS] and distance DFS [DDFS]), PK and safety. The planned number of patients was 164 (82 in each group). Results: A total of 180 patients were enrolled from Apr 2012 to Feb 2013 and 167 patients were randomized. We compared 83 patients in 6MG (age: mean 44.2; SD 4.90) and 84 patients in 3MG (44.0; 5.18). There were no significant differences in background factors between the groups. 6MG showed non-inferior suppression of serum E2 levels to 3MG (See Table). Serum LH and FSH levels were also decreased. DFSs and DDFSs at 96 weeks after randomization were similar in both groups. A double-peak PK profile and sustainable release of the study drug for 24 weeks were found with 6MG. All-grade adverse events (AEs) occurred in 98.8% and 97.6% and grade 3 or higher AEs in 18.1% and 21.4% with 6MG and 3MG, respectively. There were no significant differences in lumbar spine bone mineral density change rates in both groups. Table Serum E2 suppression rate based on the menopausal level (≤30 pg/mL) from 4 to 48 weeks after the first administration 6MG (n = 83)3MG (n = 84)Serum E2 suppression rate (%) (95% CI)97.6 (91.565, 99.707)96.4 (89.916, 99.257)6MG − 3MG (95% CI)1.2 (−5.241, 7.806)Note: Noninferiority margin of 10%. Conclusion: This first clinical study of TAP-144-SR(6M) in premenopausal breast cancer patients showed clinically noninferior serum E2 suppression levels to TAP-144-SR(3M), and no significant safety differences between the groups. TAP-144-SR(6M) was confirmed to have excellent usability in premenopausal breast cancer patients after surgery, and is considered valuable for the appropriate treatment of these patients. Citation Format: Kurebayashi J, Toyama T, Sumino S, Fujimoto T. Hormone dynamics, pharmacokinetics, safety and efficacy of leuprorelin acetate 6-month depot formulation and tamoxifen adjuvant endocrine therapy combination in premenopausal patients with hormone receptor-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-07.

Efficacy and tolerability of 3- and 6-month depot formulations of leuprorelin acetate for advanced prostate cancer in treatment-naïve and pretreated patients: pooled data from two non-interventional studies.

e16098 Background: Androgen-deprivation therapy is the current standard therapy for advanced prostate cancer (PCa), primarily consisting of injections of luteinizing hormone-releasing hormone agoni...

Are PSA baseline levels an indicator for suitability of intermittent androgen deprivation in patients with PSA relapse after radical prostatectomy?

136 Background: Intermittent androgen deprivation (IAD) for prostate cancer patients is currently discussed as a treatment option to improve quality of life and to delay hormone resistance. So far only limited data are available indicating whether certain subgroups of patients with PSA relapse without local recurrence after radical prostatectomy are best suited for this therapy. Methods: In a prospective randomized phase III trial, men with unfavourable prognostic factors and a systemic PSA progression (PSA ≥ 1ng/ml) following an initial fall to < 0.5 ng/ml within 3 months after radical prostatectomy were enrolled. They underwent a 6-months androgen deprivation (AD) induction phase with a microencapsulated leuprorelin acetate 3-month depot formulation plus an overlapping antiandrogen to prevent tumor flare-up. Achieving a PSA level < 0.5 ng/ml, they were randomized to either an IAD treatment arm or to continuous AD. In the IAD arm, retreatment was started when PSA rose to ≥ 3 ng/ml. During Off-Treatment-Time (OTT) PSA and Testosterone were controlled on a monthly basis. Results: Analysis of the first IAD cycle, confined as induction phase + OTT, revealed two subgroups of patients with a cycle length ≤ 15 months (group 1) and ≥ 20 months (group 2) respectively. This was due to a significant difference in the time from testosterone normalization (≥ 2.3 ng/ml, TN) to an increased PSA-value ≥ 3 ng/ml. See Table. Conclusions: Our data show a significant (p=0.001) relationship of low PSA baseline levels to delayed biochemical PSA progression during OTT. Thus IAD might be most suitable for patients with low PSA baseline levels leading to a slow increase of PSA after TN during OTT, providing time to improve quality of life and delay potential hormone resistance. Further large scale studies will be necessary to confirm our findings. Clinical trial information: AP 06/95.[Table: see text]

P110 Efficacy and tolerability of 3- and 6-month depot formulations of leuprorelin acetate for advanced prostate cancer in daily clinical practice: Pooled data from 2 non-interventional studies

P110 Efficacy and tolerability of 3- and 6-month depot formulations of leuprorelin acetate for advanced prostate cancer in daily clinical practice: Pooled data from 2 non-interventional studies

Efficacy and Safety of Leuprolide Acetate 3-Month Depot 11.25 Milligrams or 30 Milligrams for the Treatment of Central Precocious Puberty

GnRH agonist (GnRHa) monthly injections are frequently used in the treatment of central precocious puberty (CPP). The 3-month leuprolide depot 11.25- and 30-mg formulations are newly approved treatment options. The aim of the study was to investigate the safety and efficacy of leuprolide acetate 3-month depot formulations for the treatment of CPP in children. This was a phase III, randomized, open-label, dose-ranging 6-month study. Twenty-two U.S. medical centers (including Puerto Rico) participated. Children diagnosed with CPP (n = 84), who were either treatment naive or previously treated with GnRHa, were recruited. Chronological age at onset of pubertal signs was less than 8 yr in girls and less than 9 yr in boys, and bone age was advanced over chronological age at least 1 yr. Leuprolide acetate depot (11.25 or 30 mg) was administered im every 3 months. Biochemical [peak-stimulated LH, estradiol (girls), and testosterone (boys)] and anthropometric (growth rate, bone age acceleration, pubertal progression) parameters and safety were assessed. Peak-stimulated LH was suppressed in the 11.25- and 30-mg dose groups in 78.4 and 95.2%, respectively, of children from months 2 through 6. There were nine treatment failures (peak-stimulated LH >4 IU/liter) in the 11.25-mg group and two in the 30-mg group. Basal sex steroid suppression, growth rates, pubertal progression, bone age advancement, and adverse events were similar with either dose. Treatment with leuprolide acetate 3-month depot formulations (11.25 and 30 mg) effectively suppressed the GnRH axis, was well tolerated, and may positively impact patient convenience and compliance.

Efficacy and safety of leuprolide acetate 6-month depot for suppression of testosterone in patients with prostate cancer

Background:This open-label study evaluated the efficacy and safety of a new leuprolide acetate 45 mg 6-month depot formulation in 151 men with prostate cancer who received 2 intramuscular injections administered 24 weeks apart.Methods:The primary efficacy measurement was the proportion of patients achieving suppression of serum testosterone to ⩽50 ng dl−1 from week 4 through week 48. Adverse events (AEs) and hormonal and safety laboratory values were monitored.Results:The primary efficacy end point was achieved in 93.4% of subjects (95% confidence interval (89.2%, 97.6%)). There were nine escapes from testosterone suppression during the study, none of which were accompanied by a rise in PSA. By week 4, mean testosterone concentration was suppressed below castrate levels to 15.9 ng dl−1; suppression was maintained for the entire 24-week duration of each depot injection. No mean increase in testosterone was observed after the second injection. Mean PSA levels were maintained below 3 ng ml−1 from week 14 through the 48-week treatment period. The most frequent AE was flushing (58.3%). Injection site reactions were reported in 24.5% of patients.Conclusions:Leuprolide acetate 45 mg 6-month depot demonstrated rapid and sustained testosterone suppression through 12 months and was well tolerated. This 6-month leuprolide acetate depot will decrease the number of annual injections in the treatment of prostate cancer.

A 6-month depot formulation of leuprolide acetate is safe and effective in daily clinical practice: a non-interventional prospective study in 1273 patients

BackgroundTestosterone stimulates growth in many prostate tumours. The established GnRH analogue leuprolide acetate is incorporated in a novel biodegradable polymer matrix (Atrigel® delivery system), that can be administered to reduce testosterone levels in men with advanced hormone-dependent prostate cancer. This novel formulation is available as a 1-, 3- and most recently 6-month depot (Eligard® 45 mg). The latter was shown to lower and maintain safe and effective serum testosterone suppression in a clinical study.MethodsA non-interventional study to confirm the efficacy and safety of 6-monthly leuprolide acetate (Eligard® 45 mg) in routine urological practice was performed in Germany. Data were obtained from 1273 patients under the care of 634 urologists, and were analysed descriptively. Concentrations of PSA and serum testosterone were documented at the baseline visit and at 6 and 12 months following 6-monthly leuprolide acetate. The participating physicians were also asked to assess the efficacy, tolerabilty and handling of 6-monthly leuprolide acetate.ResultsSerum concentrations of PSA and testosterone were decreased substantially within 6 months of initial 6-monthly leuprolide acetate administration. At 12 months, median reductions of 96% (to 0.5 ng/ml) in PSA, and 90% (to 8.9 ng/dl) in serum testosterone, were observed. Further PSA and serum testosterone decreases were also observed in a subpopulation of patients who switched to 6-monthly leuprolide acetate from other GnRH analogues. Physicians rated 6-monthly leuprolide acetate as easy to use, and patients reported good tolerability. Adverse events occurred in 9% of patients; the majority were not serious. In particular, low rates of hot flushes were reported.ConclusionsThis non-interventional study showed that the reliable reduction of PSA and testosterone levels demonstrated in previous clinical studies of twice-yearly leuprolide acetate can also be achieved in routine clinical practice. This study also confirmed good tolerability of 6-monthly leuprolide acetate in routine clinical use and received positive appraisal from physicians.

A Randomized Trial of 1- and 3-Month Depot Leuprolide Doses in the Treatment of Central Precocious Puberty

To compare 1-month and 3-month depot formulations of leuprolide acetate (DL), a gonadotropin-releasing hormone analog, in the treatment of central precocious puberty (CPP). Subjects with CPP naïve to therapy were randomized to 7.5 mg of 1-month DL, 11.25 mg of 3-month DL, or 22.5 mg of 3-month DL. Stimulated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and estradiol levels, growth velocity, and bone age progression were examined in a 2-year period. Forty-nine female and 5 male subjects with CPP were randomized. Mean stimulated LH and FSH levels during treatment were higher in the low-dose 11.25-mg 3-month DL group, and more LH levels >4 IU/L were observed, in comparison with the other two dose groups. Mean LH and FSH levels in the 22.5-mg 3-month group were not different from the monthly DL. No differences in estradiol levels, growth velocity, or bone age progression were observed in dosing groups. All DL doses resulted in prompt and effective suppression of puberty, but higher LH and FSH levels were seen with the 11.25-mg 3-month DL dose. Multi-monthly DL is effective in treating CPP, but higher dosing may be required in some circumstances.

LEUPRORELIN ACETATE DEPOT (ELIGARD) IN THE TREATMENT OF PROSTATE CANCER: WHAT DO PATIENTS WIN?

Eligard (leupropelin acetate, Atrigel delivery system) is a synthetic analogue of luteinizing-hormone-realizing hormone (LHRH), which causes a rapid reduction in the level of testosterone to the concentration comparable with that after surgical castration. Eligard demonstrated a considerable advantage over other LHRH analogues in the depth of androgenic suppression and in the frequency of transient increases in testosterone levels at the beginning and during therapy. Eligard is available as 1-, 3-, and 6-month depot formulations, which allows a flexible approach to be applied to individually making up a therapy regimen. Eligard is as effective as castration therapy techniques. Treatment with this drug shows the low frequency of side effects and is well tolerated by patients.

Safety and clinical efficacy of a new 6-month depot formulation of leuprorelin acetate in patients with prostate cancer in Europe

This multicentre European study compared the safety and tolerability of the existing 11.25 mg 3-month depot of leuprorelin acetate with a new 30 mg 6-month depot in men with newly diagnosed prostate cancer or prostate-specific antigen relapse after radiotherapy or prostatectomy. The primary end points were safety and tolerability and secondary end points were clinical response based on European Organization for Research and Treatment of Cancer (EORTC) criteria and response rate by time point for testosterone suppression (castrate level <or=50 ng per 100 ml). Results showed that the incidence of adverse events was similar with the different depot formulations, with hot flushes being the most common. The assessment of EORTC response criteria showed comparable results in each arm with a tumour progression rate of <10% at the final examination at month 12. Testosterone suppression was comparable with the different formulations. In conclusion, the 6-month depot formulation of leuprorelin acetate containing 30 mg is well tolerated and safe and has been shown to be as effective as the widely used 3-month depot containing 11.25 mg leuprorelin acetate in the treatment of prostate cancer.

The relationship between LHRH-agonist depot formulations and frequency of follow-up with health care providers in patients with prostate cancer

16002 Background: Several formulations of Luteinizing Hormone-Releasing Hormone Agonists (LHRH-A) of varying duration are available for treatment of prostate cancer (PCa). Previous reports suggest that utilization of longer acting LHRH-A may reduce the number of healthcare visits, thereby reducing the costs of managing PCa patients. In this study we investigated the frequency of patient follow-up with respect to use of 1, 3 and 4 month depot formulations in a cohort of patients with PCa from a large healthcare system in the United States. Methods: Data from PCa patients identified in the Henry Ford Health System (HFHS) as International Classification of Diseases for Oncology (ICD-O) code C61.9 in the tumor registry were extracted. The following patients were included: full staging information at index and the same dosage of LHRH-A during the duration of the follow-up. Patients with prior primary tumor types were excluded. Results: 653 patients receiving the same depot of LHRH-A through the duration of agonist treatment were identified (44.1 % Caucasians, mean age 72±9.2, mean Gleason score 7.2, median PSA 10.5). There was no significant difference with depot switchers excluded from the analysis. Patients receiving 1, 3 and 4-month depot formulations had 25, 29 and 41 days between any PCa related visits. Patients on the 1-month depot had 51 days between visits to urologists, while patients on 3 and 4 month depots had 46 and 60 days between urologist visits, respectively. For patients receiving 1-month depot, there was no significant difference between the actual time between PCa related follow-up visits and expected time between follow-up visits (mean difference -5 days; p=0.1923). However, patients receiving 3-month (mean difference -61 days; p<0.0001) and 4-month (mean difference -79 days; p<0.0001) depot formulations had significantly less time than expected between PCa related follow-up visits. Conclusions: Although it was expected that the depot formulation would have a significant impact on the interval between PCa related visits, the data did not support this. The results of this study suggest that patients’ frequency of follow- up with health care providers is not influenced by LHRH-A depot formulations. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ferring Ferring Ferring Ferring