Clinical Pharmacokinetics

, Volume 41, Issue 7, pp 485–504

Clinical Pharmacokinetics of Depot Leuprorelin

  • Piero Periti
  • Teresita Mazzei
  • Enrico Mini
Review Article Drug Disposition


Leuprorelin acetate is a synthetic agonist analogue of gonadotropin-releasing hormone. Continued leuprorelin administration results in suppression of gonadal steroid synthesis, resulting in pharmacological castration.

Since leuprorelin is a peptide, it is orally inactive and generally given subcutaneously or intramuscularly. Sustained release parenteral depot formulations, in which the hydrophilic leuprorelin is entrapped in biodegradable highly lipophilic synthetic polymer microspheres, have been developed to avoid daily injections. The peptide drug is released from these depot formulations at a functionally constant daily rate for 1, 3 or 4 months, depending on the polymer type [polylactic/glycolic acid (PLGA) for a 1-month depot and polylactic acid (PLA) for depot of >2 months], with doses ranging between 3.75 and 30mg.

Mean peak plasma leuprorelin concentrations (Cmax) of 13.1, 20.8 to 21.8, 47.4, 54.5 and 53 µg/L occur within 1 to 3 hours of depot subcutaneous administration of 3.75, 7.5, 11.25, 15 and 30 mg, respectively, compared with 32 to 35 µg/L at 36 to 60 min after a subcutaneous injection of 1mg of a non-depot formulation. Sustained drug release from the PLGA microspheres maintains plasma concentrations between 0.4 and 1.4 µg/L over 28 days after single 3.75, 7.5 or 15mg depot injections.

Mean areas under the concentration-time curve (AUCs) are similar for subcutaneous or intravenous injection of short-acting leuprorelin 1mg; a significant dose-related increase in the AUC from 0 to 35 days is noted after depot injection of leuprorelin 3.75, 7.5 and 15mg. Mean volume of distribution of leuprorelin is 37L after a single subcutaneous injection of 1mg, and 36, 33 and 27L after depot administration of 3.75, 7.5 and 15mg, respectively. Total body clearance is 9.1 L/h and elimination half-life 3.6 hours after a subcutaneous 1mg injection; corresponding values after intravenous injection are 8.3 L/h and 2.9 hours.

A 3-month depot PLA formulation of leuprorelin acetate 11.25mg ensures a Cmax of around 20 µg/L at 3 hours after subcutaneous injection, and continuous drug concentrations of 0.43 to 0.19 µg/L from day 7 until before the next injection.

Recently, an implant that delivers leuprorelin for 1 year has been evaluated. Serum leuprorelin concentrations remained at a steady mean of 0.93 µg/L until week 52, suggesting zero-order drug release from the implant.

In general, regular or depot leuprorelin treatment is well tolerated. Local reactions are more common after application of the 3- or 4-month depot in comparison with the 1-month depot.


  1. 1.
    Belchetz PE, Plant TM, Nakai Y, et al. Hypophysiological responses to continuous and intermittent delivery of hypothalamic gonadotropin-releasing hormone. Science 1978; 202: 631–41PubMedCrossRefGoogle Scholar
  2. 2.
    Henzl MR. Gonadotropin-releasing hormone and its analogues: from laboratory to bedside. Clin Obstet Gynecol 1993; 36(3): 617–35PubMedCrossRefGoogle Scholar
  3. 3.
    Alberts B, Bray D, Lewis J, et al. The cell. 2nd ed. New York: Garland Publishing, 1989Google Scholar
  4. 4.
    Conn PM, Hazem E. Luteinizing hormone release and gonadotropin-releasing hormone (GnRH) receptor internalization independent actions of GnRH [letter]. Endocrinology 1982; 109: 2040Google Scholar
  5. 5.
    Stojilkovic SS, Rojas E, Stutzin A, et al. Desensitization of pituitary gonadotropin secretion by agonist-induced inactivation of voltage-sensitive calcium channels. J Biol Chem 1989; 264: 10939–42PubMedGoogle Scholar
  6. 6.
    Conn PM, Crowley WF. Gonadotropin-releasing hormone and its analogues. N Engl J Med 1991; 324(2): 93–103PubMedCrossRefGoogle Scholar
  7. 7.
    Karten MJ, Rivier JE. Gonadotropin-releasing hormone analog design. Structure-function studies toward the development of agonists and antagonists: rationale and perspective. Endocr Rev 1986; 7: 44–66PubMedCrossRefGoogle Scholar
  8. 8.
    Lønning PE, Lien EA. Pharmacokinetics of anti-endocrine agents. In: Workman P and Graham MA, guest editors. Cancer surveys, vol 17: pharmacokinetics and cancer chemotherapy 1993. New York: CSHL Press, 1993Google Scholar
  9. 9.
    Fujino M, Fukuda T, Shinagawa S, et al. Synthetic analogs of luteinizing hormone-releasing hormone (LH-RH) substituted in position 6 and 10. Biochem Biophys Res Commun 1974; 60: 406–13PubMedCrossRefGoogle Scholar
  10. 10.
    Handelsman DJ, Swerdloff RS. Pharmacokinetics of gonadotropin-releasing hormone and its analogs. Endocr Rev 1986; 7(1): 95–101PubMedCrossRefGoogle Scholar
  11. 11.
    Plosker GL, Brogden RN. Leuprorelin. A review of its pharmacological and therapeutic use in prostatic cancer, endometriosis and other sex hormone-related disorders. Drugs 1994; 48(6): 930–67Google Scholar
  12. 12.
    Ascoli M, Segaloff DL. Adenohypophyseal hormones and their hypothalamic releasing factors. In: Hardman JG, Goodman Gilman A, Limbird LE, editors. The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 1363–80Google Scholar
  13. 13.
    Lu MF, Lee D, Rao GS. Percutaneous absorption enhancement of leuprolide. Pharm Res 1992; 9(12): 1575–9PubMedCrossRefGoogle Scholar
  14. 14.
    Perrin MH, Rivier JE, Vale WW. Radioligand assay for gonadotropin-releasing hormone: relative potencies of agonists and antagonists. Endocrinology 1980; 106: 1289–93PubMedGoogle Scholar
  15. 15.
    Rizzo M, Mazzei T, Mini E, et al. Leuprorelin acetate depot in advanced prostatic cancer: a phase II multicenter trial. J Int Med Res 1990; 18 Suppl. 1: 114–25PubMedGoogle Scholar
  16. 16.
    Covens A, Thomas G, Shaw P, et al. A phase II study of leuprolide in advanced/recurrent endometrial cancer. Gynecol Oncol 1997; 64(1): 126–9PubMedCrossRefGoogle Scholar
  17. 17.
    Kuhn JM, Abourachid H, Brucher P, et al. A randomized comparison of the clinical and hormonal effects of two GnRH agonists in patients with prostate cancer. Eur Urol 1997; 32(4): 397–403PubMedGoogle Scholar
  18. 18.
    Horwich A, Huddart RA, Gadd J, et al. A pilot study of intermittent androgen deprivation in advanced prostate cancer. Br J Urol 1998; 81(1): 96–9PubMedCrossRefGoogle Scholar
  19. 19.
    Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprorelide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol 1998; 91(1): 16–24Google Scholar
  20. 20.
    Sharifi R, Soloway M, and the Leuprolide Study Group. Clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol 1990; 143: 68–71PubMedGoogle Scholar
  21. 21.
    Sharifi R, Bruskewitz RC, Gittleman MC, et al. Leuprolide acetate 22.5 mg 12-week depot formulation in the treatment of patients with advanced prostate cancer. Clin Ther 1996; 18(4): 647–57PubMedCrossRefGoogle Scholar
  22. 22.
    Sharifi R, Knoll LD, Smith J, et al. Leuprolide acetate (30-mg depot every four months) in the treatment of advanced prostate cancer. Urology 1998; 51(2): 271–6PubMedCrossRefGoogle Scholar
  23. 23.
    Tunn UW, Bargelloni U, Cosciani S, et al. Comparison of LHRH analogue 1-month depot and 3-month depot by their hormone levels and pharmacokinetic profile in patients with advanced prostate cancer. Urol Int 1998; 60 Suppl. 1: 9–16PubMedCrossRefGoogle Scholar
  24. 24.
    Jocham D. Leuprorelin three-month depot in the treatment of advanced and metastatic prostate cancer: long-term follow-up results. Urol Int 1998; 60 Suppl. 2: 18–24PubMedCrossRefGoogle Scholar
  25. 25.
    Fowler JE Jr, Gottesman JE, Reid CF, et al. Safety and efficacy of an implantable leuprolide delivery system in patients with advanced prostate cancer. J Urol 2000; 164: 730–4PubMedCrossRefGoogle Scholar
  26. 26.
    Fowler JE Jr, Flanagan M, Gleason DM, et al. Evaluation of an implant that delivers leuprolide for 1 year for the palliative treatment of prostate cancer. Urology 2000; 55: 639–42PubMedCrossRefGoogle Scholar
  27. 27.
    Sennello LT, Finley RA, Chu SY, et al. Single-dose pharmacokinetics of leuprolide in humans following intravenous and subcutaneous administration. J Pharm Sci 1986; 75(2): 158–60PubMedCrossRefGoogle Scholar
  28. 28.
    Stetler-Stevenson MA, Fluoret G, Nakamura S, et al. In vivo metabolism of tritiated LHRH by the whole kidney and individual tubules of rats. Am J Physiol 1983; 244: F628–32PubMedGoogle Scholar
  29. 29.
    Adjei A, Sundberg D, Miller J, et al. Bioavailability of leuprolide acetate following nasal inhalation delivery to rats and healthy humans. Pharm Res 1992; 9: 244–9PubMedCrossRefGoogle Scholar
  30. 30.
    Chrisp P, Sorkin EM. Leuprorelin: a review of its pharmacology and therapeutic use in prostatic disorders. Drugs Aging 1991; 1(6): 487–509PubMedCrossRefGoogle Scholar
  31. 31.
    Qiu Y, Johnson HW, Reiland TL, et al. Sublingual absorption of leuprolide: comparison between human and animal models. Int J Pharm 1999; 179: 27–36PubMedCrossRefGoogle Scholar
  32. 32.
    Okada U, Yamamoto M, Heya T, et al. Drug delivery using biodegradable microspheres. J Control Release 1994; 28: 121–9CrossRefGoogle Scholar
  33. 33.
    Okada H, Toguchi H. Biodegradable microspheres in drug delivery. Crit Rev Ther Drug Carrier Syst 1995; 12(1): 1–99PubMedCrossRefGoogle Scholar
  34. 34.
    Ogawa Y, Okada H, Yamamoto M, et al. In vivo release profiles of leuprolide acetate from microcapsules prepared with polylactic acids or copoly(lactic/glycolic) acids and in vivo degradation of these polymers. Chem Pharm Bull (Tokyo) 1988; 36: 2576–81CrossRefGoogle Scholar
  35. 35.
    Ogawa Y, Yamamoto M, Okada H, et al. A new technique to efficiently entrap leuprolide acetate into microcapsules of polyactic acid or copoly(lactic/glycolic) acid. Chem Pharm Bull (Tokyo) 1988; 36: 1095–103CrossRefGoogle Scholar
  36. 36.
    Ogawa Y, Okada H, Heya T, et al. Controlled release of LHRH agonist, leuprolide acetate, from microcapsules: serum drug level profiles and pharmacological effects in animals. J Pharm Pharmacol 1989; 41: 439–44PubMedCrossRefGoogle Scholar
  37. 37.
    Okada H. Once-month release injectable microspheres of leuprolide acetate, a superactive agonist of LH-RH. Proc Int Symp Control Rel Bioact Mater 1989; 16: 12–3Google Scholar
  38. 38.
    Okada H, Heya T, Igari Y, et al. One-month release injectable microspheres of leuprolide acetate inhibit steroidogenesis and genital organ growth in rats. Int J Pharm 1989: 231-9Google Scholar
  39. 39.
    Burton KW, Shameem M, Thanoo BC, et al. Extended release peptide delivery systems through the use of PLGA microsphere combinations. J Biomater Sci Polym Ed 2000; 11(7): 715–29PubMedCrossRefGoogle Scholar
  40. 40.
    Ravivarapu HB, Moyer KL, Dunn RL. Parameters affecting the efficacy of a sustained release polymeric implant of leuprolide. Int J Pharm 2000; 194(2): 181–91PubMedCrossRefGoogle Scholar
  41. 41.
    Ravivarapu HB, Moyer KL, Dunn RL. Sustained suppression of pituitary-gonadal axis with an injectable, in situ forming implant of leuprolide acetate. J Pharm Sci 2000; 89(6): 732–41PubMedCrossRefGoogle Scholar
  42. 42.
    Ravivarapu HB, Lee H, DeLuca PP. Enhancing initial release of peptide from poly(d, 1-lactide-co-glycolide) (PLGA) microspheres by addition of a porosigen and increasing drug load. Pharm Dev Technol 2000; 5(2): 287–96PubMedCrossRefGoogle Scholar
  43. 43.
    Okada H, Inoue Y, Ogawa Y, et al. Three-month release injectable microspheres of leuprorelin acetate. Proc Int Symp Control Rel Bioact Mater 1992; 19: 52–3Google Scholar
  44. 44.
    Okada H, Doken Y, Ogawa Y, et al. Preparation of three-month depot injectable microspheres of leuprorelin acetate using biodegradable polymers. Pharm Res 1994; 11: 1143–7PubMedCrossRefGoogle Scholar
  45. 45.
    Okada H, Doken Y, Ogawa Y, et al. Sustained suppression of the pituitary-gonadal axis by leuprorelin three-month depot microspheres in rats and dogs. Pharm Res 1994; 11: 1199–203PubMedCrossRefGoogle Scholar
  46. 46.
    Toguchi H. Formulation study of leuprorelin acetate to improve clinical performance. Clin Ther 1992; 14 Suppl. A: 121–30PubMedGoogle Scholar
  47. 47.
    Ogawa Y, Yamamoto M, Takada S, et al. Controlled-release of leuprolide acetate from polyactic acid or copoly(lactic/glycolic) acid microcapsules: influence of molecular weight and copolymer ratio of polymer. Chem Pharm Bull (Tokyo) 1988; 36(4): 1502–7CrossRefGoogle Scholar
  48. 48.
    Choi SH, Park TG. Hydrophobie ion pair formation between leuprolide and sodium oleate for sustained release from biodegradable polymeric microspheres. Int J Pharm 2000; 203: 193–202PubMedCrossRefGoogle Scholar
  49. 49.
    Okada H, Yamazaki I, Takatsura Y, et al. Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (Leuprolide) in rats. IV: evaluation of the vaginal absorption and gonadotropin responses by radioimmunoassay. J Pharm Sci 1984; 73(3): 298–302Google Scholar
  50. 50.
    Okada H, Yamazaki I, Yashiki T, et al. Vaginal absorption of a potent luteinizing hormone-releasing hormone analogue (leuprolide) in rats. II: mechanism of absorption enhancement with organic acids. J Pharm Sci 1983; 72(1): 75–8Google Scholar
  51. 51.
    Shimamoto T. Pharmaceutical aspects: nasal and depot formulations of leuprolide. J Androi 1987; 8(1): S14–6Google Scholar
  52. 52.
    Yamazaki I. Serum concentration patterns of an LHRH agonist, gonadotrophins and sex steroids after subcutaneous, vaginal, rectal and nasal administration of the agonist to pregnant rats. J Reprod Fert 1984; 72: 129–36CrossRefGoogle Scholar
  53. 53.
    Meyer BR, Kreis W, Eschbach J, et al. Successful transdermal administration of therapeutic doses of polypeptide to normal human volunteers. Clin Pharmacol Ther 1988; 44(6): 607–12PubMedCrossRefGoogle Scholar
  54. 54.
    Okada H, Heya T, Ogawa Y, et al. One-month release injectable microcapsules of a luteinizing hormone-releasing hormone agonist (leuprolide acetate) for treating experimental endometriosis in rats. J Pharmacol Exp Ther 1988; 244: 744–50PubMedGoogle Scholar
  55. 55.
    Yamazaki I, Okada H. A radioimmunoassay for a highly active luteinizing hormone-releasing hormone analogue and relation between the serum level of the analogue and that of gonadotropin. Endocrinol Jpn 1980; 27: 593–605PubMedCrossRefGoogle Scholar
  56. 56.
    Okada H, Inoue Y, Heya T, et al. Pharmacokinetics of once-a-month injectable microspheres of leuprolide acetate. Pharm Res 1991; 8: 787–91PubMedCrossRefGoogle Scholar
  57. 57.
    Okada H, Heya T, Ogawa Y, et al. Sustained pharmacological activities in rats following single and repeated administration of once-a-month injectable microspheres of leuprolide acetate. Pharm Res 1991; 8: 584–7PubMedCrossRefGoogle Scholar
  58. 58.
    Okada H, Doken Y, Ogawa Y. Persistent suppression of the pituitary-gonadal system in female rats by three-month depot injectable microspheres of leuprorelin acetate. J Pharm Sci 1996; 85(10): 1044–8PubMedCrossRefGoogle Scholar
  59. 59.
    Fornara P, Jocham D. Clinical study results of the new formulation leuprorelin acetate three-month depot for the treatment of advanced prostate carcinoma. Urol Int 1996; 56 Suppl. 1: 18–22PubMedCrossRefGoogle Scholar
  60. 60.
    Cho NB, Harada M, Imaeda T, et al. Discovery of a novel, potent and orally active nonapeptide antagonist of the human luteinizing hormone-releasing hormone (LHRH) receptor. J Med Chem 1998; 41(22): 4190–5PubMedCrossRefGoogle Scholar
  61. 61.
    Imai K, Yamanaka H, Yuasa H, et al. The sustained release of LH-RH agonist from LH-RH agonist-polymer composite in patients with prostatic cancer. Prostate 1986; 8: 325–32PubMedCrossRefGoogle Scholar
  62. 62.
    Mazzei T, Mini E, Eandi M, et al. Pharmacokinetics, endocrine and antitumour effects of leuprolide depot (TAP- 144-SR) in advanced prostatic cancer: a dose-response evaluation. Drugs Exp Clin Res 1989; XV(8): 373–87Google Scholar
  63. 63.
    Mazzei T, Mini E, Rizzo M, et al. Human pharmacokinetic and pharmacodynamic profiles of leuprorelin acetate depot in prostatic cancer patients. J Int Med Res 1990; 18 Suppl. 1: 42–56PubMedGoogle Scholar
  64. 64.
    Khan MS, O’Brien A. An evaluation of pharmacokinetics and pharmacodynamics of leuprorelin acetate 3M-depot in patients with advanced and metastatic carcinoma of the prostate. Urol Int 1998; 60(1): 33–40PubMedCrossRefGoogle Scholar
  65. 65.
    Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 1984; 311: 1281–6CrossRefGoogle Scholar
  66. 66.
    Ueno H, Matsuo S. High-performance liquid chromatography followed by radioimmunoassay for the determination of a luteinizing hormone-releasing hormone analogue, leuprorelin, and its metabolite. J Chromatogr 1991; 566: 57–66PubMedCrossRefGoogle Scholar
  67. 67.
    Marshall JC, Odell WD. Preparation of biologically active [125I]LH-RH suitable for membrane binding studies. Proc Soc Exp Biol Med 1975; 149(2): 351–5PubMedGoogle Scholar
  68. 68.
    Giraud B. Interim report of a large French multicentre study of efficacy and safety of 3.75 mg leuprorelin depot in metastatic prostatic cancer. J Int Med Res 1990; 18 Suppl. 1: 84–9PubMedGoogle Scholar
  69. 69.
    Kienle E, Lübben G, The German Leuprorelin Study Group. Efficacy and safety of leuprorelin acetate depot for prostate cancer. Urol Int 1996; 56 Suppl. 1: 23–30PubMedCrossRefGoogle Scholar
  70. 70.
    Harris KA, Small EJ. Hormonal treatment for prostate cancer. Expert Opin Investig Drugs 2001; 10(3): 493–510PubMedCrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Piero Periti
    • 1
  • Teresita Mazzei
    • 1
  • Enrico Mini
    • 1
  1. 1.Department of Preclinical and Clinical PharmacologyUniversità di FirenzeFirenzeItaly

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