1. 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) PAGE 2007, København, Denmark 13 June 2007 (1) LAP&P Consultants BV (2) PK-PD / M&S, Clinical Pharmacology &Kinetics, Organon

2. 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. 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. 4 Endocrine regulation of the male reproductive system Brain LHFSH Lydig cells Sertoli cells Testes T - inhibin - - GnRH + Hypotalamus Anterior pituitary exogenous T progestogen T

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

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

7. 7 Model structure DSG/ENG plus TD/TE exogenous T dLH/dt = Kin LH. 1/T. (1-Effect LH ) – kout LH. LH dFSH/dt = Kin FSH. 1/T. (1-Effect FSH ) – kout FSH. FSH dT/dt = k infusion T + Kin T.LH – kout T.T T T LH FSH Kin kout Kin kout - - - - + DSG / ENG

8. 8 Visual predictive checks (1) Brady et al, 2006 baseline 1-4 weeks 1 measurement 48 weeks32 weeks ENG implant (day 1) washout LH FSH T... 400 mg TD / 6 weeks

9. 9 Visual predictive checks (2) Wu et al, 1999 baseline 1-4 weeks 1-2 measurements 22 days20 weeks24 weeks 300 ug DSG o.d. washout FSH T. LH.. 50 mg TE / week

10. 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. 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. T T LH FSH Kin kout Kin kout - - + Androgen Kinfusionke - - - -

12. 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. 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. 14 Acknowledgments

15. 15

16. 16 Back up slides

17. 17 Study data Trial publicationNo. of subjTreat. periodTreatment not published9 1 ½ weeks (10 days) 300 µg DSG (o.d.) Cathy et al, 200512048 weeks 300 µg ENG (o.d.) + 400 mg TD (once/4 weeks) 300 µg ENG (o.d.) + 400 mg TD (once/6 weeks) Brady et ai, 200612048 weeks ENG implants (once) + 400 mg TD (once/4 weeks) ENG implants (once) + 400 mg TD (once/6 weeks) ENG implants (once) + 600 mg TD (once/6 weeks) Wu et al, 1999*2424 weeks 300 µg DSG (o.d.) + 100 mg TE (once a week) 300 µg DSG (o.d.) + 50 mg TE (once a week) 150 µg DSG (o.d.) + 100 mg TE (once a week) Anawalt et al, 20002424 weeks 300 µg DSG (o.d.) + 100 mg TE (once a week) 150 µg DSG (o.d.) + 100 mg TE (once a week) 150 µg DSG (o.d.) + 50 mg TE (once a week) Baseline Treatment Wash out

18. 18 Individual plots Wu et al, 1999 : Dose TE: 50 mg/week; Dose DSG:300 ug

19. 19 Model applicability in drug development (2) Elucidation of underlying mechanisms: Hypothesis: inhibition of SHBG concentrations would partly justify the greater Effect LH and Effect FSH extent after co-administration of T and progestogen. T T LH FSH Kin kout Kin kout - - + SHBG Kin kout + + - - - Kinf T +

20. 20 Elucidation of underlying mechanisms: Inhibition of SHBG concentrations partially justified the amplified progesterone effect on LH and FSH Model applicability in drug development (2)

21. 21 Effect of T on LH and FSH (check assumption) WHO, 1996 Dose TE: 200 mg/week Further mechanistic refinement dLH/dt = Kin LH. 1/T. (1-Effect LH ) – kout LH. LH dFSH/dt = Kin FSH. 1/T. (1-Effect FSH ) – kout FSH. FSH