Clinical Pharmacokinetics of Depot Leuprorelin
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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.
- 3.Alberts B, Bray D, Lewis J, et al. The cell. 2nd ed. New York: Garland Publishing, 1989Google Scholar
- 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
- 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
- 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.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
- 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
- 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.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
- 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
- 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.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.Shimamoto T. Pharmaceutical aspects: nasal and depot formulations of leuprolide. J Androi 1987; 8(1): S14–6Google Scholar
- 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