A pharmacokinetic and pharmacodynamic study of desmopressin: evaluating sex differences and the effect of pre-treatment with piroxicam, and further validation of an indirect response model

Abstract

Desmopressin is a synthetic vasopressin analogue mainly used in treatment of diabetes insipidus and nocturia. Studies in rats have revealed a sex difference in the response to a vasopressin infusion, which was diminished after treatment with an NSAID. This study was performed in man to investigate the influence of sex and concomitant treatment of piroxicam on the pharmacokinetics and dynamics of desmopressin, and to validate a previously described indirect response model. Eight healthy males and eight healthy females participated in the trial, which was conducted in a pharmacokinetic (PK) part followed by a pharmacodynamic (PD) part. Desmopressin was administered intravenously as a single dose (PK = dose 2 microg, PD = dose 0.2 microg). Piroxicam was administered to achieve steady state. The pharmacokinetic parameters of desmopressin were estimated and calculated by means of two-compartmental analysis. In the dynamic part a study design based on an oral hydration model was used. Parameters for urine flow and urine osmolality were estimated. Individual estimates of the pharmacokinetic parameters served as input to the indirect response model that subsequently was fitted to urine osmolality data. The pharmacokinetics of desmopressin after a fixed bolus injection was neither influenced by piroxicam nor sex of the subject. The pharmacodynamics of desmopressin showed a sex difference where females exhibited a more pronounced antidiuretic effect than males, which was statistically significant when the effects were submaximal (>4.5 h after dose). The sex differences were diminished after pre-treatment with piroxicam, indicating a prostaglandin PGE(2)-mediated mechanism. The indirect response model was confirmed, although the modelling could not distinguish a sex difference, indicating a limitation of this model compared with traditional descriptive statistics.

Temporal delays and individual variation in antidiuretic response to desmopressin

“…It has previously been shown that urine osmolality vs. desmopressin concentration over time is consistent with an indirect-response model (7,23)…”

“…A previous study in water-loaded healthy adults has shown that a bolus injection of a large dose of desmopressin produces a rise in urine osmolality that reaches a maximum ϳ4 h after plasma desmopressin has begun to fall (7). With this kind of delay (also termed hysteresis from the Greek word meaning "coming late"), an indirect-response pharmacokinetic (PK)/pharmacodynamic (PD) model in which the agonist is assumed to inhibit elimination of the response provides a good fit to the urine osmolality data and has been used previously to characterize the PD response to desmopressin (7,23). However, these studies did not address the cause of the delay, the effect of dose or the extent of individual differences, all of which are important for the use of desmopressin in physiological and pathophysiological research as well as clinical diagnosis and treatment.…”

Gender differences in kidney function

“…Furthermore, in rats, dogs, and humans, blood pressure, urine flow, osmolarity, and water clearance exhibit gender differences (M>F), possibly due to higher sensitivity of the M gender to vasopressin; M contain higher density of vasopressin V 2 receptors in the collecting duct cells and exhibit higher vasopressin-induced antidiuresis than F [182,[271][272][273]. However, another study on healthy men and women, who were treated with a synthetic vasopressin, desmopressin, revealed just opposite gender-dependent vasopressin action: F exhibited a more pronounced antidiuretic response than M [173].…”

Doping control analysis of desmopressin in human urine by LC‐ESI‐MS/MS after urine delipidation

“…For this reason, the World Anti-Doping Agency (WADA) has added desmopressin to the Prohibited List as a masking agent and, consequently, methods for detection of desmopressin need to be developed to control its misuse (WADA, 2011). Several detection methods using immunoassays for plasma and urine have been described (Lundin et al, 1985;Fjellestadpaulsen et al, 1993;Agerso et al, 2004;Odeberg et al, 2004;Osterberg et al, 2006). These methods are very sensitive but do not always provide the high grade of specificity and selectivity necessary in doping control analysis.…”