Skip to main content
SpringerLink
Log in

Population Pharmacokinetic/ Pharmacodynamic Modeling of Cetrorelix, a Novel LH-RH Antagonist, and Testosterone in Rats and Dogs

  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose. Population models for thepharmacokinetic-pharmacodynamic relationship for cetrorelix (CET), a luteinising hormone-releasinghormone (LH-RH) antagonist, and the pharmacodynamic response ontestosterone production were investigated in rats and dogs.

Methods. The plasma concentrations of CET and testosterone weredetermined after intravenous and subcutaneous injections. Thepopulation PK/PD-models were developed using P-PHARM software.

Results. Absolute bioavailability of cetrorelix was 100% in rats and97% in dogs. In rats, the pharmacokinetics was explained by atwo-compartment model with saturable absorption, while athree-compartment model was used in dogs. Testosterone suppression in both specieswas described by a sigmoid Emax model with maximum effect (Emax)considered as total hormonal suppression. The duration of testosteronesuppression in rats was longer at higher doses. The populationelimination half-lifes after iv-dose were 3.0 h in rats and 9.3 h in dogs.Population mean estimates of IC50 were 1.39 and 1.24 ng/ml in ratsand dogs, respectively.

Conclusions. A population pharmacokinetic model was developed toexplain the dissolution rate limited absorption from the injection site.The suppression of testosterone could be described by an indirectinhibitory sigmoid Emax model. In both species 1-2 ng/ml CET inplasma was necessary to suppress testosterone production.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  1. E. Knobil. The neuroendocrine control of the menstrual cycle. Recent Prog. Horm. Res., 36:53-80 (1980).

    Google Scholar 

  2. S. Fukuda. Circadian rhythm of serum testosterone levels in male beagle dogs-effects of lightning time zone. Exp. Anim., 39(1):65-68 (1990).

    Google Scholar 

  3. L. R. DePalatis, J. Moore, and R. E. Falvo. Plasma concentrations of testosterone and LH in the male dog. J. Reprod. Fert., 52: 201-207 (1978).

    Google Scholar 

  4. S. Bajusz, M. Kovacs, M. Gazdag, L. Bokser, T. Karashima, V. J. Csernus, T. Janaky, J. Guoth, and A. V. Schally. Highly potent antagonists of luteinizing hormone-releasing hormone free of edematogenic effects. Proc. Natl. Acad. Sci. USA 85:1637-1641 (1988).

    Google Scholar 

  5. M. Schwahn, P. Romeis, G. Peter, H. Derendorf, and M. Herbst. Absolute bioavailability and dose proportionality of CET, a novel LH-RH antagonist, in male and female rats. Arch. Pharmacol. 355(4):R8 (1997).

    Google Scholar 

  6. H. Berger, N. Heinrich, H. Schäfer, I. Baeger, and B. Mehlis. Gonadotropin-releasing hormone (GnRH) pharmacokinetics: peptide hormone pharmacokinetics needs clarification. Life Sci. 42:985-991 (1988).

    Google Scholar 

  7. N. I. Chu, R. L. Chan, K. M. Hama, and M. D. Chaplin. Disposition of Narfarelin acetate, a potent luteinizing hormone-releasing hormone agonist, in rats and rhesus monkeys. Drug Metab. Dispos. 13:560-565 (1985).

    Google Scholar 

  8. H. Berger, N. Heinrich, E. Albrecht, U. Kertscher, J. Oehlke, M. Bienert, H. Schäfer, I. Baeger, and B. Mehlis. Gonadotropin-releasing hormone (GnRH) analogs: relationship between their structure, proteolytic inactivation and pharmacokinetics in rats. Regul. Pept. 33:299-311 (1991).

    Google Scholar 

  9. E. Ezan, K. Drieu, M. Chapelat, C. Rougeot, and F. Dray. Radioimmunoassay of [D-Trp6]-luteinizing hormone releasing hormone: its application to animal pharmacokinetic studies after single injection and long-acting formulation administration. Regul. Pept. 14:155-167 (1986).

    Google Scholar 

  10. H. Okada, Y. Inoue, T. Heya, H. Ueno, Y. Ogawa, and H. Touchi. Pharmacokinetics of once-a-month injectable microspheres of leuprolide acetate. Pharm. Res. 8:787-791 (1991).

    Google Scholar 

  11. E. Hudon, J. J. Rondeau, V. Lenaerts, P. Wüthrich, F. Boutignon, R. Deghenghi, S. Marleau, N. Yamagutchi, A. Adam, and H. Ong. Radioimmunoassay of meterelin and pharmacokinetics after single injection and implant administration in dogs. J. Pharm. Sci. 86:172-178 (1997).

    Google Scholar 

  12. F. Haviv, E. N. Bush, J. Knittle, and J. Greer. LHRH Antagonists. In Borchard (eds), Integration of pharmaceutical discovery and development, Plenum Press, New York, 1998.

    Google Scholar 

  13. S. Sorensen, J. J. Rondeau, V. Lenaerts, F. Boutignon, P. Wüthrich, R. Deghenghi, A. Adam, and H. Ong. Radioimmunoassay of antarelix, a luteinising hormone releasing-hormone antagonist, in plasma and its application for pharmacokinetic study in dogs. J. Immunoassay 17:205-226 (1996).

    Google Scholar 

  14. R. L. Chan, W. Ho, A. S. Webb, J. A. LaFargue, and C. A. Nerenberg. Disposition of detirelix, a potent luteinising hormone-releasing hormone antagonist, in rats and monkeys. Pharm. Res. 5:335-340 (1988).

    Google Scholar 

  15. R. L. Chan, S. C. Hsieh, P. E. Haroldsen, W. Ho, and J. J. Nestor, Jr. Disposition of RS-26306, a potent luteinizing hormone-releasing hormone antagonist, in monkeys and rats after single intravenous and subcutaneous administration. Drug Metab. Dispos. 19:858-864 (1991).

    Google Scholar 

  16. V. J. Csernus, B. Szende, K. Groot, T. W. Redding, and A. V. Schally. Development of radioimmunoassay for a potent luteinizing hormone-releasing hormone antagonist. Drug Res. 40: 111-118 (1990).

    Google Scholar 

  17. H. H. Raffel, M. Locher, H. O. Borbe. High-performance liquid chromatographic assay for the determination of the decapeptide cetrorelix, a novel luteinizing hormone-releasing hormone antagonist, in human plasma. J Chromatography B. 653:102-105 (1994).

    Google Scholar 

  18. M. Gibaldi and D. Perrier. Pharmacokinetics. 2nd Ed. Marcel Dekker Inc., 1982, pp. 155-161.

  19. N. L. Dayneka, V. Garg, and W. J. Jusko. Comparison of four basic models of indirect pharmacodynamic responses. J. Pharmacokin Biopharm. 21:457-478 (1993).

    Google Scholar 

  20. F. Mentre and R. Gomeni. A two step iterative algorithm for estimation in nonlinear mixed-effect models with an evaluation in population pharmacokinetics. J. Biopharm. Stat. 5:141-158 (1995).

    Google Scholar 

  21. User Manual, P-Pharm, (Ver. 1.5), Innaphase, Champs sur Marne, France (1994).

  22. A. Bartke, R. E. Steele, N. Musto, and B. V. Caldwell. Fluctuations in plasma testosterone levels in adult male rats and mice. Endocrinol. 92:1223-1228 (1973).

    Google Scholar 

  23. A. R. Günzel-Apel, H. G. Brinckmann, and H. O. Hoppen. Dynamics of LH and testosterone secretion in male beagles of different age. Reprod. Dom. Anim. 25:78-86 (1990).

    Google Scholar 

  24. J-M. Gries, A. Munafo, H. C. Porchet, and D. Verotta. Down-regulation models and modeling of testosterone production induced by recombinant human choriogonadotropin. J. Pharmacol. Exp. Ther. 289:371-377 (1999).

    Google Scholar 

  25. G. Halmos, A. V. Schally, J. Pinski, M. Vadillo-Buenfil, and K. Groot. Down-regulation of pituitary receptors for luteinizing hormone-releasing hormone (LH-RH) in rats by LH-RH antagonist Cetrorelix. Proc. Natl. Acad. Sci. USA 93:2398-2402 (1996).

    Google Scholar 

  26. K. E. Fattinger, D. Verotta, H. C. Porchet, A. Munafo, J-Y. Le Cotonnec, and L. B. Sheiner. Modeling a bivariate control system: LH and testosterone response to the GnRH antagonist antide. Am. J. Physiol. 271:E775-E787 (1996).

    Google Scholar 

  27. A. Lasdun, S. Reznik, C. J. Molineaux, and M. Orlowski. Inhibition of endopeptidase 24.15 slows the in vivo degradation of luteinizing hormone-releasing hormone. J. Pharmacol. Exp. Ther. 251:439-447 (1989).

    Google Scholar 

  28. B. Horsthemke, H. Knisatschek, J. Rivier, J. Sandow, and K. Bauer. Degradation of luteinizing hormone-releasing hormone and analogs by adeno-hypophyseal peptidases. Biochem. Biophys. Res. Commun. 100:753-759 (1981).

    Google Scholar 

  29. K. Hakola, D. Pierroz, A. Aebi, B. A. M. Vuagnat, M. L. Aubert, and I. Huhtaniemi. Dose and time relationship of intravenously injected rat recombinant luteinizing hormone and testicular testosterone secretion in the male rat. Biol. Reproduction 59:338-343 (1998).

    Google Scholar 

  30. B. W. Knol, S. J. Dielemann, M. M. Bevers, and W. E. van den Brom. GnRH in the male dog: dose-response relationship with LH and testosterone. J. Reprod. Fert. 98:159-161 (1993).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Research Biochemistry, Corporate Research & Development, ASTA Medica Group, Weismüllerstraβe 45, D-60314, Frankfurt/Main, Germany

    Martin Schwahn

  2. College of Pharmacy, Department of Pharmaceutics, Health Science Centre, University of Florida, Gainesville, Florida, 32610-0494

    Nelamangala V. Nagaraja & Hartmut Derendorf

Authors
  1. Martin Schwahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nelamangala V. Nagaraja
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hartmut Derendorf
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schwahn, M., Nagaraja, N.V. & Derendorf, H. Population Pharmacokinetic/ Pharmacodynamic Modeling of Cetrorelix, a Novel LH-RH Antagonist, and Testosterone in Rats and Dogs. Pharm Res 17, 328–335 (2000). https://doi.org/10.1023/A:1007557207590

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1007557207590

Search

Navigation