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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.

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gender differences in v2 agonists with focus on polyuric conditions

Gender Differences in V2 AgonistsWith focus on polyuric conditions

Dr. Kristian Vinter Juul, D.V.M

PhD-student University of Ghent

Medical Science Director Medical Science Urology Ferring International PharmaScienceCentre Copenhagen

female rats express significantly more v2r mrna
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]

Liu J, et al: Sex Differences in Vasopressin V2 Receptor Expression and Vasopressin-InducedAntidiuresis. Am J Physiol Renal Physiol December 1, 2010

slide3

Gender difference "masked" by high exposure?

Figure 1, Dose/Response curve for dDAVP/AVP)

slide4

X-Escape and AVPR2

The V2-receptor is located on the X-chromosome:

It is possible that the gene for V2 can escape inacti-vation. This will give higher density of receptors in women and a greater response to Desmopressin

slide6

Data used in this exploratory analysis

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.

slide7

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

slide9

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

slide13

Long-term durability of gender difference confirmed

Mean decrease in # nocturnal voids

Mean decrease in number of nocturnal voids (25–50 µg ODT) was greater for females than males

Juul et al, NAU, 2012

slide16

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

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