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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)
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
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.
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
17
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
19
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
21
• 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)
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