Mechanism-based model of effect of co-administration of exogenous testosterone and progestogens on the hypogonadal axis in men

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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) LAPP Consultants BV (2) PK-PD / MS,
Clinical Pharmacology Kinetics, Organon
PAGE 2007, København, Denmark 13 June 2007
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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

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Study data
Baseline
Treatment
Wash out

• 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)

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Endocrine regulation of the male reproductive
system
Brain
-
Hypotalamus
GnRH

progestogen
Anterior pituitary
-
-
inhibin
LH
FSH

Testes
exogenous T
T
Lydig cells
Sertoli 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
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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
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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
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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
FSH
LH
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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 lt 12)
• Kouts fixed at stage 2 of model development

except for the parameter that describes the
effect after administration of DSG only (CV68)
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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
LH
kout
-
-
Kinfusion
ke
Androgen

Kin
T
kout
-
-
Kin
kout
FSH
-
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Model applicability in drug development

• Prediction of the effect of newly developed
  androgens
• Androgen steady state concentrations of 0.3
  nmol/L is required

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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)

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Acknowledgments
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(No Transcript)
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Back up slides
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Study data
Baseline
Treatment
Wash out
Trial publication No. of subj Treat. period Treatment
not published 9 1 ½ weeks (10 days) 300 µg DSG (o.d.)
Cathy et al, 2005 120 48 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, 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)
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Individual plots
Wu et al, 1999 Dose TE 50 mg/week Dose
DSG300 ug
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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.

-
kout
Kin
LH

-
-
Kin
kout
SHBG


Kin
kout
T
Kinf T
-

Kin
kout
FSH
-
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Model applicability in drug development (2)

• Elucidation of underlying mechanisms
• Inhibition of SHBG concentrations partially
  justified the amplified progesterone effect on LH
  and FSH

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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