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
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 - PowerPoint PPT Presentation
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1
Mechanism-based model of effect of co-administration of exogenous testosterone
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
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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
+
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• Elucidation of underlying mechanisms:
• Inhibition of SHBG concentrations partially justified the amplified progesterone effect on LH and FSH