Extended release, 6-month formulations of leuprolide acetate for the treatment of advanced prostate cancer: achieving testosterone levels below 20 ng/dl

Crawford, E. David; Moul, Judd W.; Shore, Neal D.

doi:10.1517/17425255.2015.1073711

Cited by 22 publications

(23 citation statements)

References 46 publications

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“…[1] A number of luteinizing hormone-releasing hormone (LHRH) analogs, for example, leuprolide acetate, have been developed for this purpose. [1][2][3] In men, LHRH secreted in the hypothalamus stimulates the production of luteinizing hormone in the pituitary, which in turn, stimulates the secretion of testosterone in the testis. [2,3] LHRH agonists, such as leuprolide, have a high affinity for LHRH receptors in the pituitary.…”

Section: Doi: 101002/mabi202000050mentioning

confidence: 99%

“…A few long-acting depot formulations have been developed using this approach. [1,2,[6][7][8][9][10][11][12][13][14] Although these drug carriers can extend the duration of drug action, their pharmacokinetic profiles are far from perfect. For example, for the PLGA microparticle approach, a characteristic tri-phased release, which is characterized by an initial burst release followed by a slow release phase and a final rapid release phase, is usually observed.…”

Section: Doi: 101002/mabi202000050mentioning

confidence: 99%

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Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Zhuang²,

Zhang³

et al. 2020

Macromolecular Bioscience

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Leuprolide has been widely used in androgen deprivation therapy for the treatment of advanced prostate cancer, but its use is still limited due to its short half‐life. Herein, hydrogen‐bonded layer‐by‐layer films are fabricated from PEGylated leuprolide (PEG‐LEU) and tannic acid (TA). Because of its dynamic nature, the film disintegrates gradually in water and releases PEG‐LEU and TA. The in vitro release profile indicated perfect zero‐order kinetics, which is explained by the unique release mechanism. When implanted subcutaneously in male rats, the films maintain a constant serum drug level. For a 60‐bilayer film, the serum drug level is maintained constant for ≈24 days. No initial burst release is observed, suggesting that the in vivo release also follows zero‐order kinetics. Initially, an increase in the level of serum testosterone is induced by the released drug, followed by testosterone suppression to a constant level below the castrate level, which could be maintained as long as a constant serum drug level is maintained. Since the new drug carriers avoid an initial burst release of the drug and maintain a constant serum drug level and hence a constant serum testosterone level below the castrate level, these carriers are highly promising for androgen deprivation therapy.

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Section: Doi: 101002/mabi202000050mentioning

confidence: 99%

Section: Doi: 101002/mabi202000050mentioning

confidence: 99%

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Zhuang²,

Zhang³

et al. 2020

Macromolecular Bioscience

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“…given Leuprorelin (Leuprolide) by S/c at a dose 0.07 mg/kg twice weekly for 35 days after PCOS induction by DHA, according to (Crawford et al, 2015).…”

Section: Experimental Designmentioning

confidence: 99%

Biochemical effect of leuprolide, cabergoline and some herbals on ameliorating polycystic ovaries syndrome

Abouzaid

A.H

A.A.

et al. 2018

Benha Veterinary Medical Journal

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A B S T R A C TPolycystic ovary syndrome (PCOS) is a set of symptoms due to elevated androgens\in females. Its Signs include irregular or no menstrual periods, heavy periods, excess body and facial hair, acne, pelvic pain, difficulty getting pregnant, and patches of thick, darker, velvety skin. It could be a result from the combination of genetic and environmental factors. Many drugs used for treating this disease. Several hormones have been measured to evaluate PCOS (progesterone, Estradiol, Follicular Stimulating Hormone (FSH), Luteinizing hormone (LH), Total Testosterone, Anti-Mullerian Hormone (AMH), Thyroid Stimulating Hormone (TSH), Prolactin and histopathological studies. Groups were classified as follow: Group (1) Control, Group (2) Dehydroepiandrosterone (DHEA only), Group (3) (DHEA and flaxseed), Group (4) (DHEA and alfalfa), Group (5) (DHEA and Soya), Group (6) (DHEA and Cabergoline), and Group (7) (DHEA and Leuproline). Results: DHEA in a dose of (1mg/kg) induced PCOS and it was clear by significant elevation of (LH/ FSH ratio, total testosterone, AMH, TSH, Prolactin) and a significant decrease in progesterone and estradiol. Leuproline was the best choice to decrease the symptoms of PCOS followed by cabergoline and the least but still effective were the herbals (Soya, flaxseed, and alfalfa). In conclusion, DHEA could be used for PCOS induction, Leuproline, cabergoline and phytoestrogen containing herbals could be used for treating PCOS symptoms.

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“…Leuprolide acetate (LA) is the most widely used GnRH agonist15 and is available in depot formulations allowing for administration every 1, 3, 4, or 6 months, depending on the formulation and/or dose 10,15. These depot formulations are of two types: intramuscularly-administered LA-containing microspheres16 and a subcutaneously-administered biodegradable LA-containing polymer solid 17.…”

Section: Introductionmentioning

confidence: 99%

“…Given the current interest in testosterone suppression to levels ≤20 ng/dL rather than the 50 ng/dL threshold during ADT,10 we carried out a retrospective analysis of two Phase III trials to examine the ability of 4- and 6-month LA intramuscular, microsphere depot formulations (Lupron ® , AbbVie, North Chicago, IL, USA) to achieve testosterone castrate levels ≤20 ng/dL.…”

Section: Introductionmentioning

confidence: 99%

Intramuscular depot formulations of leuprolide acetate suppress testosterone levels below a 20 ng/dL threshold: a retrospective analysis of two Phase III studies

Spitz

Gittelman

Karsh

et al. 2016

RRU

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IntroductionAndrogen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) analogs is a standard treatment for advanced prostate cancer. GnRH analog therapy can reduce testosterone to “castrate” levels, historically defined as <50 ng/dL. With the advent of newer assays, a lower threshold of <20 ng/dL has recently been proposed. We report the results of a retrospective analysis of two Phase III trials of 4- and 6-month depot microsphere formulations of leuprolide acetate (LA), a GnRH agonist that has previously demonstrated efficacy in testosterone suppression to <50 ng/dL in patients on ADT. This analysis investigates the ability of these LA formulations to suppress to ≤20 ng/dL levels.MethodsIn two of five AbbVie/Abbott clinical trials of microsphere formulations of LA for ADT, analytic technology permitting testosterone detection as low as 3 ng/dL was used and thus was selected for this analysis. Both trials were open-label, fixed-dose studies in prostate cancer patients, naïve to ADT. Patients received either 30 mg (4-month formulation; n=49) or 45 mg (6-month formulation; n=151) depot injections of LA microspheres. Treatment duration was up to 32 weeks for the 4-month formulation and 48 weeks for the 6-month formulation. The proportion of patients achieving the 20 ng/dL threshold was determined every 4 weeks.ResultsPooled analysis showed that 152 of 193 (79%) of patients achieved serum testosterone levels of ≤20 ng/dL at 4 weeks, and sustained the improvement at week 24 (169/189, 89%). Additionally, in the 6-month study, 127/135 (94.1%) patients were suppressed to ≤20 ng/dL at 48 weeks.ConclusionBoth 4- and 6-month intramuscular depot formulations of LA achieved and maintained mean serum testosterone levels ≤20 ng/dL in the vast majority of patients as early as 4 weeks following treatment initiation. Additional research on the clinical relevance of this lower testosterone threshold is warranted.

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Extended release, 6-month formulations of leuprolide acetate for the treatment of advanced prostate cancer: achieving testosterone levels below 20 ng/dl

Abstract: As the understanding of optimal T castrate level evolves and may be refined pending new data from contemporaneous trials, achievement and maintenance of T levels well below 50 ng/dl may be important in evaluating potential differences in ADT regimens.

Cited by 22 publications

References 46 publications

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Hydrogen‐Bonded Films for Zero‐Order Release of Leuprolide

Biochemical effect of leuprolide, cabergoline and some herbals on ameliorating polycystic ovaries syndrome

Intramuscular depot formulations of leuprolide acetate suppress testosterone levels below a 20 ng/dL threshold: a retrospective analysis of two Phase III studies

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