BERKELEY, CA (UroToday.com) - This is the first evaluation of gender effects in efficacy of long-term use of desmopressin for nocturia. Our paper reports a pooled analysis of long-term data from efficacy studies of desmopressin orally disintegrating tablet (ODT; 25, 50 or 100 μg) and desmopressin solid tablet (100, 200 or 400 μg) in nocturia. In light of recent findings that females have a higher renal sensitivity to desmopressin, we also investigated the presence of any gender differences during prolonged treatment.
We found that ODT decreased mean number of nocturnal voids over time with a dose–response effect (mean reductions of 1.4-2.1 at 52 weeks across doses), and somehow, unexpectedly, we also observed an indication of increased efficacy with increased time on treatment. A clear gender difference was also seen at lower doses of desmopressin ODT with mean decrease in nocturnal voids and increased undisturbed sleep greater for females than for males. In contrast, patients treated with tablet, at higher exposure, showed a more modest decrease in mean number of nocturnal voids over time (mean reductions of 1.0-1.8 at 40 weeks) with no clear dose-response effect. No gender difference in reduction in nocturnal voids was seen at any dose level for the tablet.
|"The finding reveals a potential clinical benefit of enabling the specific tailoring of antidiuretic treatments for both men and women..."|
These results immediately raise the question of why no dose-response effect or gender difference was seen in the tablet studies. Recent ODT trials in nocturia have found increased reductions in nocturnal voids at lower doses than with the tablet, especially in females, who appear more sensitive to desmopressin’s antidiuretic action. As authors of this paper, we suggest that the lack of a clear dose-response with the tablet is due to reaching the upper asymptote of the dose-response curve with doses around and above 100-μg tablet. This would also account for a lack of gender difference in effect.
The reasons for this gender effect, that has only become evident over the last couple of years, are yet not fully understood and require further investigation. Likely explanation is sex hormones altering sensitivity to vasopressin, and possibly to desmopressin as well, and/or genetics since the arginine vasopressin receptor 2 gene (AVPR2) is located on the X chromosome and may escape X inactivation. Thus, females may have higher levels of AVPR2 expression than males, which may explain their increased response to desmopressin. To our knowledge, a gender difference affecting clinical efficacy and safety in the magnitude that we have found with desmopressin in this analysis and in other works (in our first reporting we found relative male/female sensitivity of desmopressin on antidiuretic effect of 2.7 and risk of hyponatremia up to five-fold higher for females compared to males ), is rather unprecedented compared to other marketed drugs. The finding reveals a potential clinical benefit of enabling the specific tailoring of antidiuretic treatments for both men and women, improving the therapeutic windows for each gender.
Another important clinical question arising from the results is: What are the possible mechanisms behind increasing efficacy with increasing duration of treatment? The results of our analysis suggest that additional clinical benefit is achieved with persistence with desmopressin treatment. As authors, we speculate that desmopressin may influence long-term alterations in the hormonal control of water homeostasis, thereby causing greater efficacy with time. Clearly, further studies are needed to determine optimal treatment duration.
Finally, a relevant methodological question to our paper is the well-known difficulties associated with interpretation of open-label extension studies. Patients who choose to continue into open-label extension studies may differ, in clinically important ways, from those who drop out, leading to a selected patient group continuing with the study. Once a trial becomes open-label, it is also possible that patients report greater efficacy because they know they are on active treatment. In nocturia, symptoms may fluctuate or resolve over time, rendering treatment unnecessary. However, we were keen to analyse for this potential source of bias, and in the current study, efficacy not only endured, but increased with time, and most importantly, no difference was found between all patients and patients who completed the long-term study, suggesting differences between completers and dropouts were not responsible for the increased efficacy of desmopressin during long-term treatment.
- Juul KV, Klein BM, Sandström R, Erichsen L, Nørgaard JP: Gender Difference in Antidiuretic Response to Desmopressin. Am J Physiol Renal Physiol. 2011 May;300(5):F1116-22. Epub 2011 Mar
Kristian Vinter Juul,* Bjarke M. Klein, and Jens Peter Nørgaard as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Ferring International PharmaScience Center, Copenhagen S, Denmark
*Ferring International PharmaScience Center, Kay Fiskers Plads 11, 2300 Copenhagen S, Denmark.
Disclosures: The authors are employees of Ferring Pharmaceuticals.