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Gender Differences in V2 Agonists
With focus on polyuric conditions
Dr. Kristian Vinter Juul, D.V.M
PhD-student University of Ghent
Medical Science Director Medical Science Urology
Ferring International PharmaScience
Centre Copenhagen
Female rats express significantly more V2R mRNA
 Liu et al 2010: Female rats
express significantly more
V2R mRNA and protein in
kidneys than males
 Hypothesis: this results
physiologically in a greater
sensitivity to V2R agonist
administration[1]
1.
Liu J, et al: Sex Differences in Vasopressin V2 Receptor Expression and Vasopressin-Induced
Antidiuresis. Am J Physiol Renal Physiol December 1, 2010
Slide 2
Gender difference "masked" by high exposure?
Figure 1, Dose/Response curve for dDAVP/AVP)
Normal
Uosm (mosmol/kg)
1200
1000
800
600
400
200
0
1
2
3
4
Plasma AVP/dDAVP (pg/ml)
Urine concentration
Slide 3
13
X-Escape and AVPR2
The V2-receptor is located on the X-chromosome:
It is possible that the gene
for V2 can escape inactivation. This will give higher
density of receptors in
women and a greater
response to Desmopressin
Slide 4
Slide 5
Data used in this exploratory analysis
Study Number of subjects
(males/females)
CS29 757 ITT subjects
710 completed part I
341 females
416 males
Treatments
Placebo
Desmopressin
administered as an
oral lyophilisate
(10, 25, 50 or 100
μg)
Data included in this
analysis*)
PD/safety:
Nocturnal urine volume
(average of 3 nights)
pre-dose and day 28
and serum sodium levels
pre-dose, days 4, 8, 15,
22, and 28.
CS20 28 healthy volunteers Single-dose
desmopressin
14 males
administered as
14 females
MINIRIN tablets
(2x0.2 mg) in one
treatment period
and as an oral
lyophilisate of
240 µg in another
treatment period
PK: plasma
desmopressin
concentrations, 0-14
hours post-dosing
CS21 25 healthy volunteers Single-dose
desmopressin
15 males
administered as an
10 females
oral lyophilisate of
60 µg, 120 µg or
240 µg
PK: plasma
desmopressin
concentrations, 0-14
hours post-dosing
Weiss JP, Zinner NR, Klein BM, Nørgaard JP. Neurourol Urodyn. 2012 Apr;31(4):441-7. doi: 10.1002/nau.22243. Epub 2012 Mar 22.
Slide 6
Mean desmopressin concentration profiles by
dose and gender, successive tests of covariates
log(age), gender, and log(weight)
Table 1: Successive tests (top-down) of covariate effects on
Desmopressin AUC and Cmax
Mean Desmopressin Concentration by Dose and Sex
Female
Male
240 ug
25
Parameter/Effect
Value
Std. error
p-value
20
Log(AUC)
15
Log(AGE)
0.305245
0.268562
0.2612
10
Sex
-0.213592
0.187890
0.2610
Log(DOSE)
1.146739
0.088843
<.0001
25
Log(Weight)
-1.010370
0.518942
0.0571
20
Log(Cmax)
15
Log(AGE)
0.202791
0.215285
0.3508
10
Sex
-0.178737
0.146037
0.2267
5
log(DOSE)
1.074818
0.088482
<.0001
Log(Weight)
-0.997688
0.409185
0.0183
C o n c e n tra ti o n (p g /m L )
5
120 ug
60 ug
25
20
15
10
5
0
2
4
6
8
T ime (h)
Slide 7
10
12
14
Gender difference in CS29
D e c re a s e i n N o c tu rn a l U ri n e V o l u m e (m M )
400
Female
300
200
Male
100
0
0
20
60
40
Dose (ug)
Slide 8
80
100
Nocturnal Urine Volume
 Tests of covariate effects showed that the gender difference in
weight-corrected ED50 was statistically significant (p=0.009)
 The relative sensitivity (ED50 for males/ ED50 for females) is
estimated at 2.7 with a 95% CI of 1.3-8.1
Parameter estimates for the nocturnal urine volume model
Parameter
Emax (none)
ED50 (males) (µg)
ED50 (females) (µg)
Relative Sensitivity
(Female/Male)
 (mL)
 (none)
Residual SD
Slide 9
Estimate
0.364
43.2
16.1
2.68
SE
0.084
21.7
15.9
1.67
136
0.696
229
24.2
0.033
8.3
Slide 10
Slide 11
Slide 12
Long-term durability of gender
difference confirmed
Mean decrease in # nocturnal voids
1.
Juul et al, NAU, 2012
Slide 13
Mean decrease in
number of nocturnal
voids (25–50 µg
ODT) was greater
for females than
males
Treatment effect relative to Placebo
effect. CS40. Females
ENDPOINT
Placebo
baseline
25 µg
Baseline
Placebo 3
months
Mean (SD) Mean (SD)
#Voids
2.88 (0.798) 2.84 (0.887)
Undisturbed
Sleep (min)
33%
Responder
odds
NQoL total
Nocturnal UVol (mL)
1.
Sand et al, J Urol, 2013
25 µg 3
months
Delta Mean
Treatment
effect
relative to
Placebo
effect
Delta Mean
-1.24
-1.46
1.18
143 (57.6)
147 (56.9)
106
155
1.46
N/A
N/A
1.75
3.23
1.85
N/A
N/A
21.9
27.2
1.24
607 (338)
627 (328)
151
235
1.56
Treatment effect relative to Placebo
effect. CS41. Males
ENDPOINT
Placebo
baseline
50 µg
Baseline
Placebo3
months
Mean (SD) Mean (SD)
#Voids
Undisturbed
Sleep (min)
33%
Responder
odds
NQoL total
Nocturnal UVol (mL)
1.
Weiss et al, J Urol, 2013
Delta Mean
50 µg 3
months
Treatment effect
relative to
Placebo effect
Delta
Mean
2.90 (0.81)
2.88 (0.86)
-0.88
-1.25
1.42
147 (58)
146 (53)
73
112
1.53
N/A
N/A
1.02
2.01
1.97
N/A
N/A
13.9
18.4
1.32
620 (313)
607 (325)
131
209
1.60
Conclusion
 In conclusion, differences in pharmacodynamic response
leads to a dose recommendation in adult nocturia patients,
stratified by gender:
For females 25 µg seemed to be an optimal, efficacious and
safe dose while similar efficacy is expected for males at a
dose level approximately 2-3 times higher
Slide 16
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