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Gender Differences in V2 Agonists With focus on polyuric conditions

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

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  1. 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

  2. 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

  3. Gender difference "masked" by high exposure? Figure 1, Dose/Response curve for dDAVP/AVP)

  4. 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

  5. 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.

  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

  7. Gender difference in CS29

  8. 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

  9. 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

  10. Treatment effect relative to Placebo effect. CS40. Females Sand et al, J Urol, 2013

  11. Treatment effect relative to Placebo effect. CS41. Males Weiss et al, J Urol, 2013

  12. 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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