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Leuprorelin

A Review of its Pharmacology and Therapeutic Use in Prostatic Disorders

  • Drug Evaluation
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Summary

Synopsis

Leuprorelin (leuprolide acetate) is a synthetic analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] which initially stimulates luteinising hormone (LH) and hence testicular androgen release; continuous administration then results in profound suppression of these hormones. Testosterone levels associated with castration are attained within 3 to 4 weeks. A biodegradable subcutaneous or intramuscular depot formulation of leuprorelin 3.75 or 7.5mg, which releases the drug at a constant rate over 28 days, is available and may be preferred over daily subcutaneous injections.

The progression of previously untreated advanced prostatic cancer is delayed in 70 to 90% of men receiving leuprorelin, with median survival of approximately 2 years. The efficacy of leuprorelin is equivalent to that of estrogen therapy, but the tolerability of the GnRH analogue is far better. In contrast to most other studies of GnRH agonists, a slight survival advantage has been reported for combined treatment with leuprorelin and the antiandrogen flutamide. Small noncomparative trials reveal that leuprorelin also causes regression of benign hyperplastic prostate tissue with corresponding relief of obstructive, but not irritative, symptoms although continuous treatment is necessary to maintain remission.

Impotence and flushing occur in most leuprorelin recipients but, unlike diethylstilbestrol (stilboestrol), cardiovascular toxicity and gynaecomastia are not significant problems. Symptom flare, usually manifested as bone pain in prostate cancer patients and exacerbation of obstructive symptoms in those with benign prostatic hypertrophy, can occur in 4 to 29% at the beginning of treatment.

Leuprorelin treatment is therefore an established effective palliative measure in men with previously untreated advanced prostatic cancer, and may have a role in those with benign hypertrophy who are unfit for surgery.

Pharmacodynamic Properties

Leuprorelin (leuprolide acetate) is a synthetic agonist analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] with up to 80 to 100 times the potency of the native hormone. Administration is initially associated with stimulation of pituitary release of luteinising hormone (LH), causing an increase in testicular androgen production. Continued administration results in ‘down-regulation’ and desensitisation of pituitary GnRH receptors, and is associated with a decline in LH release and suppression of gonadal androgen synthesis.

Peak serum LH levels occur within 4 days of beginning subcutaneous leuprorelin administration in men with prostate cancer and healthy male volunteers, and usually decline thereafter with further treatment, reaching levels significantly below baseline after 2 weeks and which remain suppressed with continuous therapy. The biological activity of LH is also reduced. Although follicle-stimulating hormone (FSH) levels reach a minimum within 1 month, levels may increase again, but are still lower than pretreatment values.

The profile of LH release dictates testosterone synthesis in the testes. Therefore, serum testosterone levels reach a peak peak within 2 to 4 days of initiating leuprorelin treatment and then rapidly fall to reach levels associated with castration (< 1.7 nmol/L) within 3 to 4 weeks. This suppression has been shown to persist for up to 7 years in men with prostate cancer. Serum levels of the pharmacologically active androgen, dihydrotestosterone, parallel those of testosterone, and intratesticular and intratubular levels are profoundly depressed.

Leuprorelin inhibited growth of androgen-dependent Dunning R3327 prostate adenocarcinoma in vivo but not in vitro, suggesting an antitumour activity mediated through its effect on androgens rather than a significant direct action.

Pharmacokinetic Properties

Since it is a peptide, leuprorelin is orally inactive and thus is generally given subcutaneously or intramuscularly, although other routes are being investigated. A sustained release subcutaneous or intramuscular depot formulation, in which leuprorelin is encapsulated in biodegradable poly(d,l-lactide-co-glycolide) microspheres, has been developed to supersede daily injections. The drug is released from this formulation at a constant daily rate of 2.8% of the dose over 28 days.

Mean peak plasma leuprorelin concentrations of 13.1 and 47.4 µg/L occurred within 3 hours of depot subcutaneous administration of 3.75 and 7.5mg, respectively, compared with 32 to 35 µg/L 36 to 60 minutes after a subcutaneous injection of 1mg. Sustained drug release from the microspheres maintained plasma concentrations between 0.3 and 1.1 µg/L over 28 days after single 3.75 or 7.5mg depot injections. Mean concentrations ranged between approximately 0.4 to 0.6 µg/L during monthly administration of the depot formulation for up to 6 months.

Mean volume of distribution of leuprorelin 1mg was 37.1L after a single subcutaneous injection, and 36 and 33.5L following depot administration of 3.75 and 7.5mg, respectively. Total body clearance was 9.1 L/h, and elimination half-life 3.6 hours after subcutaneous 1mg injection, while corresponding values after intravenous 1mg injections were 8.3 L/h and 2.9 hours, respectively.

Therapeutic Use

Disease progression is delayed in approximately 70 to 90% (mean 87.5%) of men with previously untreated advanced prostate cancer by daily subcutaneous injection of leuprorelin 1 or 10mg, or monthly depot subcutaneous (or intramuscular) administration of 3.75 or 7.5mg depot. Partial responses or disease stabilisation usually each occur in about 43% of patients, and complete responses are rare. Median response duration is between 10 and 18 months, and median survival about 2 years. Bone pain is alleviated in a mean of 64.5% of symptomatic patients, and urinary symptoms in 80%; performance status improves in 42 to 81% of men. The efficacy of leuprorelin treatment in previously untreated men is comparable to that of diethylstilbestrol (stilboestrol) 1mg 3 times daily or fosfestrol (diethylstilbestrol diphosphate) 100mg 3 times daily, but the GnRH agonist has a significantly better tolerability profile.

A large, well-controlled study has demonstrated that daily subcutaneous leuprorelin plus oral treatment with the antiandrogen flutamide 250mg 3 times daily extends median progression-free survival by nearly 3 months, and median overall survival by over 7 months, representing small but significant increases. Survival advantage of combination therapy was particularly striking in a small subgroup of patients with good performance status and minimal metastatic bone involvement. However, studies combining other GnRH agonists with flutamide fail to demonstrate increased survival versus GnRH agonist alone and therefore the encouraging results obtained with leuprorelin plus flutamide require further confirmation.

In small numbers of men with benign prostatic hypertrophy, subcutaneous leuprorelin 1 mg/day reduced prostate size by 45% within 6 months, accompanied by relief of obstructive symptoms and minimal alleviation of irritative symptoms. Continuous leuprorelin treatment is necessary to maintain clinical remission, and should perhaps therefore be reserved for those patients in whom prostatectomy would present an unjustifiable risk of morbidity.

Tolerability

The adverse effects of leuprorelin are largely a result of alterations in sex hormone levels during treatment.

The initial stimulation of testosterone production which occurs in the first few days of leuprorelin treatment is associated with symptom flare in 4 to 29% of patients — usually bone pain, paraesthesiae, spinal cord compression, and dysuria from ureteric compression in patients with prostate cancer; a worsening of obstructive symptoms may occur in those with benign hyperplasia. Concomitant antiandrogen or diethylstilbestrol treatment during the first 2 weeks of leuprorelin administration reduces symptom flare.

Impotence and decreased libido are universal and hot flushes, usually mild and tolerable, occur in 35 to 71% during long term leuprorelin therapy. In contrast to estrogens, cardiovascular side effects (e.g. peripheral oedema, thrombosis, embolism, myocardial ischaemia) and gynaecomastia are rarely associated with leuprorelin. Mild nausea, diarrhoea and vomiting occur in 5 to 14% of leuprorelin recipients and local reactions (pain, fibrosis, pruritus) have been reported in 2 to 3% of men receiving the subcutaneous depot formulation.

Dosage and Administration

In men with advanced prostate cancer or benign prostastic hypertrophy, leuprorelin 3.75 or 7.5mg is administered as a subcutaneous or intramuscular biodegradable sustained release depot once every 4 weeks. The injection site should be reviewed periodically. This method of administration is superseding daily subcutaneous injections of 1mg. Caution should be exercised or other means of androgen ablation should be considered in men with prostate cancer at risk from spinal cord compression or ureteric obstruction due to symptom flare during the first 2 weeks of treatment. This may be avoided by giving concomitant antiandrogen or diethylstilbestrol 1mg 3 times daily for 1 week before and 1 week after the first leuprorelin dose.

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    Paul Chrisp & Eugene M. Sorkin

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Various sections of the manuscript reviewed by: H. Akaza, Institute of Clinical Medicine, University of Tsukuba, Tokyo, Japan; M. Amin, Department of Surgery, University of Louisville, Louisville, Kentucky, USA; G. Bonadonna, Division of Medical Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy; E.D. Crawford, Division of Colorado Health Sciences Center, Denver, Colorado, USA; B. Giraud, Urology Department, Hôpital Saint-Jacques, Clermont-Ferrand, France; P. Iversen, Department of Urology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; A.C. Levine, Division of Endocrinology, Department of Medicine, The Mount Sinai Medical Center, New York, New York, USA; T. Mazzei, Dipartimento di Farmacologia Preclinica e Clinica ‘Mario Aiazzi Mancini’, Università degli Studi di Firenze, Florence, Italy; G.P. Murphy, American Cancer Society, Atlanta, Georgia, USA; T. Niijima, Tokyo Seamen’s Insurance Hospital, Tokyo, Japan; P. Periti, Dipartimento di Farmacologia Preclinica e Clinica ‘Mario Aiazzi Mancini’, Università degli Studi di Firenze, Florence, Italy; F. Rasmussen, Department of Urology, Herlev Hospital, University of Copenhagen, Herlev, Denmark; J.A. Smith, Department of Urology, School of Medicine, Vanderbilt University, Nashville, Tennessee, USA.

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Chrisp, P., Sorkin, E.M. Leuprorelin. Drugs & Aging 1, 487–509 (1991). https://doi.org/10.2165/00002512-199101060-00008

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