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

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)

BaselineBaseline TreatmentTreatment Wash outWash out

4

Endocrine regulation of the male reproductive system

BrainBrain

LH FSH

Lydig cells Sertoli cells

Testes

T

-inhibin

-

-

GnRH+

Hypotalamus

Anterior pituitary

exogenous Texogenous T

progestogen progestogen

T

5

Model structure baseline only

TT

LHLH

FSHFSHKin kout

Kin

Kin kout

kout

-

-

+

6

Model structureDSG only

TT

LHLH

FSHFSHKin kout

Kin

Kin kout

kout

-

-

-

-

+

DSG DSG

DSGDSG

7

Model structureDSG/ENG plus TD/TE

exogenous Texogenous T

dLH/dt = KinLH . 1/T . (1-EffectLH) – koutLH . LH

dFSH/dt = KinFSH . 1/T . (1-EffectFSH) – koutFSH. FSH

dT/dt = kinfusion T+ KinT.LH – koutT.T

TT

LHLH

FSHFSHKin kout

Kin

Kin kout

kout

-

-

-

-

+

DSG / ENG DSG / ENG

DSG / ENG DSG / ENG

8

0 16 32 48 64 80Time (weeks)

0

2

4

6

8

10

LH

co

ncentr

ation (

U/L

)

0 16 32 48 64 80Time (weeks)

0

2

4

6

8

10

FS

H c

oncentr

ation (

U/L

)

0 16 32 48 64 80Time (weeks)

0

10

20

30

T c

oncentr

ation (

nm

ol/L

)

Visual predictive checks (1)

Brady et al, 2006

baselinebaseline

1-4 weeks1 measurement

48 weeks 32 weeks

ENG implant (day 1)ENG implant (day 1)washoutwashout

LH FSH

T

. .

.

400 mg TD / 6 weeks

9

4 12 20 28 36 44 52Time (weeks)

0

2

4

6

8

10

LH

concentr

ati

on (

U/L

)

4 12 20 28 36 44 52Time (weeks)

0

2

4

6

8

10

FS

H c

oncentr

ati

on (

U/L

)

4 12 20 28 36 44 52Time (weeks)

0

10

20

30

T c

oncentrati

on (

nm

ol/

L)

Visual predictive checks (2)

Wu et al, 1999

baselinebaseline

1-4 weeks1-2 measurements

22 days 20 weeks 24 weeks

300 ug DSG o.d.300 ug DSG o.d.washoutwashout

FSH

T

.LH

.

.

50 mg TE / week

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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.

TT

LHLH

FSHFSHKin kout

Kin

Kin kout

kout

-

-

+ AndrogenAndrogenKinfusion ke

-

-

-

-

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

0 6 12 18 24 30 36

time (weeks)

0

1

2

3

Horm

one

conc

entr

ation

(U/

L)

LHFSH

0 6 12 18 24 30 36

time (weeks)

0

5

10

15

Hor

mon

e co

ncen

tratio

n (n

mol

/L)

TAndrogen

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

16

Back up slides

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Study data

Trial publication No. of subj Treat. period Treatment

not published 91 ½ weeks

(10 days)300 µg DSG (o.d.)

Cathy et al, 2005 120 48 weeks300 µg ENG (o.d.) + 400 mg TD (once/4 weeks)

300 µg ENG (o.d.) + 400 mg TD (once/6 weeks)

Brady et ai, 2006 120 48 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* 24 24 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, 2000 24 24 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)

BaselineBaseline TreatmentTreatment Wash outWash out

182000 5000 8000

2000 5000 8000

Time (hours)

0

20

400

20

400

20

400

20

40

T con

centra

tion (n

mol/L)

ID: 3 ID: 5

ID: 7 ID: 11

ID: 14 ID: 18

ID: 22 ID: 24

Individual plots

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

2000 5000 8000

2000 5000 8000

Time (hours)

0

5

10

0

5

10

0

5

10

0

5

10

LH co

ncentr

ation (

U/L)

ID: 3 ID: 5

ID: 7 ID: 11

ID: 14 ID: 18

ID: 22 ID: 24

2000 5000 8000

2000 5000 8000

Time (hours)

0

5

10

0

5

10

0

5

10

0

5

10

FSH c

oncen

tration

(U/L)

ID: 3 ID: 5

ID: 7 ID: 11

ID: 14 ID: 18

ID: 22 ID: 24

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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.

TT

LHLH

FSHFSHKin kout

Kin

Kin kout

kout

-

-

+SHBGSHBGKin kout

+

+

-

-

-

Kinf T

+

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)

6000 14000 6000 14000

6000 14000

Time (hours)

40

90

40

90

40

90

SHBG

con

cent

ratio

ns n

mol

/L

ID: 1 ID: 2 ID: 3

ID: 4 ID: 5 ID: 6

ID: 7 ID: 8 ID: 10

Individual predicted

Obs

erve

d

20 40 60 80

1050

100

A

Population predicted

Obs

erve

d

20 25 30 35

1050

100

B

Time (hours)

Wei

ghte

d re

sidu

als

0 5000 10000 15000

-6-4

-20

24

6C

Population predicted

Wei

ghte

d re

sidu

als

20 25 30 35

-6-4

-20

24

6

D

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• Effect of T on LH and FSH (check assumption)

WHO, 1996

• Dose TE: 200 mg/week

Further mechanistic refinement

dLH/dt = KinLH . 1/T . (1-EffectLH) – koutLH . LHdFSH/dt = KinFSH . 1/T . (1-EffectFSH) – koutFSH. FSH

0 20 40 60 80

Time (weeks)

10

20

30

40

50

Testo

steron

e con

centr

ation

(nmo

l/L)

0 20 40 60 80

Time (weeks)

0

2

4

6

LH co

ncen

tratio

n (U/L

)

0 20 40 60 80

Time (weeks)

0

2

4

6

FSH c

once

ntrati

on (U

/L)