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Ashley Strougo (1), Jeroen Elassais-Schaap (2) Rik de Greef (2), Henk-Jan Drenth (1)

Mechanism-based model of effect of co-administration of exogenous testosterone and progestogens on the hypogonadal axis in men. Ashley Strougo (1), Jeroen Elassais-Schaap (2) Rik de Greef (2), Henk-Jan Drenth (1). (1) LAP&P Consultants BV

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Ashley Strougo (1), Jeroen Elassais-Schaap (2) Rik de Greef (2), Henk-Jan Drenth (1)

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  1. Mechanism-based model of effect of co-administration of exogenous testosterone and progestogens on the hypogonadal axis in men Ashley Strougo (1), Jeroen Elassais-Schaap (2) Rik de Greef (2), Henk-Jan Drenth (1) (1) LAP&P Consultants BV (2) PK-PD / M&S, Clinical Pharmacology &Kinetics, Organon PAGE 2007, København, Denmark 13 June 2007

  2. Aim • Development of a mechanism-based model of the homeostatic feedback relationships in the endocrinology of the male reproductive system • Modeling of the endocrinological effects following co-administration of testosterone and progestogens (“male pill”) • Prediction of the effects of newly developed androgens plus progestogens on spermatogenesis

  3. Study data • 5 clinical trials • 288 healthy male volunteers • Treatment period: 1 ½ weeks up to 48 weeks • Treatment medications: • Progestogen alone • DSG: p.o (daily) • Progestogen plus testosterone • DSG/ENG: p.o (daily), s.c (once) • TD/TE: i.m. (once/week, once/4 weeks, once/6 weeks) Baseline Treatment Wash out

  4. Endocrine regulation of the male reproductive system Brain - Hypotalamus + GnRH progestogen Anterior pituitary - - inhibin LH FSH Testes exogenous T T Sertoli cells Lydig cells T

  5. Model structure baseline only kout Kin LH - + kout Kin T - kout Kin FSH

  6. Model structureDSG only DSG - kout Kin LH - + kout Kin T - kout Kin FSH - DSG

  7. Model structureDSG/ENG plus TD/TE DSG / ENG dLH/dt = KinLH . 1/T . (1-EffectLH) – koutLH . LH - kout Kin LH - dT/dt = kinfusion T+ KinT.LH – koutT.T + kout Kin T exogenous T - kout Kin FSH - dFSH/dt = KinFSH . 1/T . (1-EffectFSH) – koutFSH. FSH DSG / ENG

  8. . . . Visual predictive checks (1) T Brady et al, 2006 baseline ENG implant (day 1) washout 400 mg TD / 6 weeks 1-4 weeks 1 measurement 48 weeks 32 weeks LH FSH

  9. . . . Visual predictive checks (2) T Wu et al, 1999 baseline 300 ug DSG o.d. washout 50 mg TE / week 1-4 weeks 1-2 measurements 22 days 20 weeks 24 weeks LH FSH

  10. Summary results • Adequate description of the time courses of LH, FSH and T after administration of DSG alone or DSG/ENG plus TE/TD: • TD formulation: T not immediately in steady state, resulting in slight bias • Co-administration of ENG/DSG with TD/TE: adequate predictions when effect of ENG/DSG on LH and FSH is amplified • Good prediction of steady-state situations (baseline, treatment period and washout) • Parameters were well estimated (CV < 12%*) • Kout’s fixed at stage 2 of model development * except for the parameter that describes the effect after administration of DSG only (CV=68%)

  11. Model applicability in drug development • Prediction of the effect of newly developed androgens plus progestogen : • Assumptions: (i) the androgen is twice as potent as T; (ii) azoospermia is achieved when LH and FSH concentrations are below 0.5 U/L. - Kin kout LH - - Kinfusion ke Androgen + Kin T kout - - kout Kin FSH -

  12. Model applicability in drug development • Prediction of the effect of newly developed androgens : • Androgen steady state concentrations of 0.3 nmol/L is required

  13. Conclusions & future applications • Achieved: • Integrated model of the major endocrine relationships of the male reproductive system • Separately accounts for the effect of progestogen and progestogen plus exogenous testosterone • Sound basis for further mechanistic refinement • Possible future applications: • by combining the data of T, LH and FSH, and making use of existent knowledge of the endocrinology of the male system this model allows: • Prediction of the effect of newly developed androgens • Elucidation of underlying mechanisms • Further development and refinement: • Inclusion of the contraceptive effect in the model (i.e. sperm-count)

  14. Acknowledgments

  15. Back up slides

  16. Study data Baseline Treatment Wash out

  17. Individual plots • Wu et al, 1999 : • Dose TE: 50 mg/week; Dose DSG:300 ug

  18. Model applicability in drug development (2) • Elucidation of underlying mechanisms: • Hypothesis: inhibition of SHBG concentrations would partly justify the greater EffectLH and EffectFSH extent after co-administration of T and progestogen. - kout Kin LH + - - kout Kin SHBG + + kout Kin T Kinf T - + kout Kin FSH -

  19. Model applicability in drug development (2) • Elucidation of underlying mechanisms: • Inhibition of SHBG concentrations partially justified the amplified progesterone effect on LH and FSH

  20. Further mechanistic refinement • Effect of T on LH and FSH (check assumption) WHO, 1996 • Dose TE: 200 mg/week dLH/dt = KinLH . 1/T . (1-EffectLH) – koutLH . LH dFSH/dt = KinFSH . 1/T . (1-EffectFSH) – koutFSH. FSH

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