Desmopressin oral lyophilisate in young children: new insights in pharmacokinetics and pharmacodynamics.

OBJECTIVE: To study the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of desmopressin (dDAVP) oral lyophilisate in children below the age of 8 years with special emphasis on age-related and size-related differences in bioavailability. DESIGN: Open label, non-randomised, interventional PK and PD trial. SETTING: Single-centre study. PATIENTS: Children (age: 6 months to 8 years) with nocturnal polyuria, including both children with uropathy or nephropathy (glomerular filtration rate >60 mL/min/1.73 m²) and children (age: 5-8 years) with severe monosymptomatic nocturnal enuresis, who were unresponsive to treatment with 400 µg of the dDAVP tablet for at least 1 month. INTERVENTIONS: After a water load, dDAVP was administered sublingually as a single dose of oral lyophilisate. Subsequently, blood and urine samples were collected until 7 hours post-administration. MAIN OUTCOME MEASURES: Non-compartmental analysis of PK parameters was performed based on dDAVP concentrations in both plasma and urine. To evaluate the effect of dDAVP lyophilisate (PD parameters), the urinary concentration capacity (urine osmolality (mOsm/kg)) and antidiuretic effect (diuresis rate (mL/kg/h)) were calculated. RESULTS: The PK data support the need for size-dependent dosing in children. Body weight was shown to be a significant covariate for apparent clearance (CL/F) and apparent volume of distribution (Vd/F). A double absorption peak of dDAVP lyophilisate in the first 2 hours post-administration was demonstrated. CONCLUSIONS: For the first time, a double absorption profile of dDAVP lyophilisate was found in children, questioning extrapolation of bioequivalence from adults towards children. Moreover, the need for size-adapted dosing regimens of dDAVP lyophilisate in young children is indicated. TRIAL REGISTRATION NUMBER: NTC02584231.

An Integrated Paediatric Population PK/PD Analysis of dDAVP: How do PK Differences Translate to Clinical Outcomes?

INTRODUCTION: The bioequivalence of two formulations of desmopressin (dDAVP), a vasopressin analogue prescribed for nocturnal enuresis treatment in children, has been previously confirmed in adults but not in children. In this study, we aimed to study the pharmacokinetics (PK) and pharmacodynamics (PD) of these two formulations, in both fasted and fed children, including patients younger than 6 years of age. METHODS: Previously published data from one PK study and one PK/PD study in children aged between 6 and 16 years were combined with a new PK/PD study in children aged between 6 months and 8 years, and analysed using population PK/PD modelling. Simulations were performed to further explore the relative bioavailability of both formulations and evaluate current dosing strategies. RESULTS: The complex absorption behaviour of the lyophilizate was modelled using a double input, linked to a one-compartmental model with linear elimination and an indirect response model linking dDAVP concentration to produced urine volume and osmolality. The final model described the observed data well and elucidated the complexity of bioequivalence and therapeutic equivalence of the two formulations. Simulations showed that current dosing regimens using a fixed dose of lyophilizate 120 µg is not adequate for children, assuming children to be in the fed state when taking dDAVP. A new age- and weight-based dosing regimen was suggested and was shown to lead to improved, better tailored effects. CONCLUSIONS: Bioequivalence and therapeutic equivalence data of two formulations of the same drug in adults cannot be readily extrapolated to children. This study shows the importance of well-designed paediatric clinical trials and how they can be analysed using mixed-effects modelling to make clinically relevant inferences. A follow-up clinical trial testing the proposed dDAVP dosing regimen should be performed. CLINICAL TRIAL REGISTRATION: This trial has been registered at www.clinicaltrials.gov (identifier NCT02584231; EudraCT 2014-005200-13).

Pharmacokinetic and Pharmacodynamic Properties of a Micro-Dose Nasal Spray Formulation of Desmopressin (AV002) in Healthy Water-Loaded Subjects.

PURPOSE: Antidiuretic therapy with desmopressin for nocturia has been hampered by formulations with high doses, low bioavailability and variable pharmacokinetics. AV002 (SER120), a novel, emulsified, microdose desmopressin nasal spray, with a permeation enhancer (cylcopentadecanolide), was developed to have pharmacokinetic characteristics suitable for nocturia treatment. METHODS: Twelve healthy subjects participated in an open-label, dose-escalating study. Water-loaded subjects were sequentially dosed every 48 h with AV002 0.5, 1.0, 2.0 µg and 0.12 µg desmopressin subcutaneous (SC) bolus injection. RESULTS: AV002 intranasal administration produced a time-to-maximum concentration (Tmax) between 15 and 30 min and a maximum concentration (Cmax) <10 pg/mL. Cmax and area under the curve showed dose proportionality. Coefficient of variation for AV002 was similar to that observed for the SC dose. Bioavailability of AV002 was approximately 8% compared to SC injection. AV002 demonstrated pharmacodynamic effects within 20 min of dosing and showed increasing magnitude and duration with escalating doses. AV002 2.0 µg had maximum median urine osmolality of 629 mOsm/kg and median urine output ≤2 mL/min for 5-6 h. CONCLUSIONS: AV002 demonstrated rapid absorption, high bioavailability, limited duration of action, and low coefficient of variation, suggesting it may be a suitable formulation for nocturia treatment. Trial registration not required (single-center, phase 1).

Discovery of Potent, Selective, and Short-Acting Peptidic V2 Receptor Agonists.

The vasopressin analogue desmopressin (desamino-d-arginine8 vasopressin, dDAVP, 1) is a potent vasopressin 2 (V2) receptor (V2R) agonist approved in many countries for the treatment of diabetes insipidus, primary nocturnal enuresis, nocturia, and coagulation disorders. Since 1 is primarily excreted via the kidneys, an age-related decline in kidney function leads to slower elimination, prolonged antidiuresis, and hyponatremia. In search of novel, potent, selective, and short-acting peptidic V2R agonists, we synthesized a series of C-terminally truncated analogues of [Val4]dDAVP, 2, modified in positions 2, 3, and 7 and/or at the disulfide bridge. The peptides were evaluated for in vitro potency at the human V2 receptor, selectivity versus the related receptors (human vasopressin 1a receptor, human vasopressin 1b receptor, and human oxytocin receptor), and pharmacokinetic profiles in rodents and other higher species. The truncated analogues show excellent potency at the V2R, increased systemic clearance, and shorter half-life in rats. Two compounds 19 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-Agm) and 38 (c(Bua-Cpa-Thi-Val-Asn-Cys)-Pro-d-Arg-NEt2) have been selected for clinical development for nocturia.

Pharmacokinetics and safety profile of desmopressin oral tablet formulations in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: Desmopressin acetate (DDAVP®) is a synthetic analogue of the pituitary hormone vasopressin. Until now, few studies of desmopressin have focused on the pharmacokinetics (PK) or food effects in Asian populations. This study aimed to assess the effect of food intake on the PK of desmopressin and bioequivalence of two tablet formulations in Chinese subjects. MATERIALS AND METHODS: A single-center, single-dose, randomized, open-label, two-period crossover study was conducted in 104 healthy Chinese volunteers under fasted or fed conditions (52 volunteers for each condition). Blood samples were collected up to 14 hours after administration of oral desmopressin tablets (0.6 mg; 0.2 mg × 3) in each period. Plasma desmopressin concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK and bioavailability parameters were calculated. Adverse events (AEs) were also recorded. RESULTS: No significant differences in mean (standard deviation, SD) PK parameters were observed between formulation 1 (F1) and formulation 2 (DDAVP®; F2) under both fasted and fed conditions. All AEs observed were mild and resolved quickly without treatment. The maximum concentration (Cmax) and area under the curve (AUC) were significantly decreased (p < 0.01) when the drug was taken with food, compared with fasted subjects. CONCLUSION: These findings suggest that both tablet formulations were well tolerated. Food can significantly decrease the exposure of desmopressin.
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Claiming desmopressin therapeutic equivalence in children requires pediatric data: a population PKPD analysis.

PURPOSE: For a new formulation of a drug, only pharmacokinetic bioequivalence with the original formulation has to be demonstrated in healthy, young adults. However, "children are not small adults," and to guarantee a safe and effective treatment, age-adapted drug development is required. Desmopressin, a vasopressin analogue prescribed for nocturnal enuresis in children, was studied as an example formulation first developed in adults and then extrapolated to a pediatric indication. METHODS: Population pharmacokinetic and pharmacodynamic modeling was used to analyze previously published desmopressin data of 18 children suffering from nocturnal enuresis. The main objective was the comparison of the therapeutic equivalence of two desmopressin formulations: tablet and lyophilisate. The measurements for pharmacokinetics and pharmacodynamics were respectively plasma desmopressin concentration and urine osmolality and diuresis. RESULTS: The half maximal inhibitory concentration for inhibition of urine production was 0.7 pg/mL lower for the lyophilisate than for the tablet. The effect of formulation on the half maximal inhibitory concentration seems to suggest that the 120-µg lyophilisate has a more pronounced effect on the urine volume and osmolality than the 200-µg tablet, even when the same exposure is achieved. CONCLUSIONS: A new indirect response model for desmopressin was constructed and validated, using a previously built pharmacokinetic model and additional pharmacodynamic data. In order to draw solid conclusions regarding the efficacy and safety of desmopressin in children, pharmacokinetics and pharmacodynamics data should be analyzed together. This study adds proof to potential differences in pediatric and adult pharmacokinetic and pharmacodynamic properties of desmopressin and exemplifies the need for pediatric clinical trials, not only for every new drug but also for every new formulation.

Desmopressin acetate nasal spray for adults with nocturia.

INTRODUCTION: Nocturia impacts 70% of individuals over age 70 years. Nocturnal polyuria is present in up to 88% of adults with nocturia, however, treatment options for reducing nighttime urine production have historically been limited to behavioral modification and off label use of timed diuretics and desmopressin. NoctivaTM (desmopressin acetate nasal spray, DANS, Serenity Pharmaceuticals, LLC) is a novel formulation of desmopressin approved by the Food and Drug Administration for the treatment of nocturia due to nocturnal polyuria in March 2017. Areas covered: Incidence and etiology of nocturia, currently available therapies (approved and off label), and pharmacokinetic, efficacy, and safety data associated with DANS. Expert commentary: DANS has been studied for the treatment of nocturia in adults over age 50 without contraindications to the use of desmopressin. 49% receiving the higher clinical dose experienced ≥50% reduction in nocturnal voids in clinical trials vs. 30% with placebo. Although nadir serum sodium <135 mmol/L was not uncommon (14%), the incidence of sodium ≤125 mmol/L was rare (1%). DANS therefore appears to benefit a significant subset of patients with nocturia while maintaining an acceptable risk profile. Given the risks of hyponatremia, education of patients and prescribers in contraindications and the importance of monitoring are paramount.

Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children.

INTRODUCTION: Desmopressin is used for treatment of nocturnal enuresis in children. In this study, we investigated the pharmacokinetics of two formulations-a tablet and a lyophilisate-in both fasted and fed children. METHODS: Previously published data from two studies (one in 22 children aged 6-16 years, and the other in 25 children aged 6-13 years) were analyzed using population pharmacokinetic modeling. A one-compartment model with first-order absorption was fitted to the data. Covariates were selected using a forward selection procedure. The final model was evaluated, and sensitivity analysis was performed to improve future sampling designs. Simulations were subsequently performed to further explore the relative bioavailability of both formulations and the food effect. RESULTS: The final model described the plasma desmopressin concentrations adequately. The formulation and the fed state were included as covariates on the relative bioavailability. The lyophilisate was, on average, 32.1 % more available than the tablet, and fasted children exhibited an average increase in the relative bioavailability of 101 % in comparison with fed children. Body weight was included as a covariate on distribution volume, using a power function with an exponent of 0.402. Simulations suggested that both the formulation and the food effect were clinically relevant. CONCLUSION: Bioequivalence data on two formulations of the same drug in adults cannot be readily extrapolated to children. This was the first study in children suggesting that the two desmopressin formulations are not bioequivalent in children at the currently approved dose levels. Furthermore, the effect of food intake was found to be clinically relevant. Sampling times for a future study were suggested. This sampling design should result in more informative data and consequently generate a more robust model.

Pharmacokinetics and Pharmacodynamics of the Oral Disintegrating Tablet of Desmopressin in Adults with Nocturnal Polyuria: A Pilot Study.

INTRODUCTION: The higher sensitivity to desmopressin (dDAVP) found in women and older patients with nocturnal polyuria (NP) has partially been unraveled, leading to adaptation of the dosage based on gender. However, besides age and gender, other factors might play a role in differences in sensitivity and side effects. The aim of this study is to design a pharmacokinetic/pharmacodynamic (PD) assay to identify appropriate treatment for different groups of patients, primarily dependent on differences in age and gender. METHODS: This interventional pilot study was carried out in Ghent University Hospital, Belgium, between 2011 and 2013. Patients with NP were subjected to a water load test (15 mL/kg), as well as an administration of 120 µg dDAVP oral disintegrating tablet (ODT) followed by blood analysis to determine plasma dDAVP levels and urine analysis for diuresis rate, osmolality, free water clearance and sodium clearance. RESULTS: Six female and six male patients were included (range 30-89 years old; mean age 69 years; SD 18). Three groups based on plasma dDAVP levels were found: (1) high (only women), (2) intermediate (only men) and (3) low plasma levels. For the nighttime samples (3-12 h after intake) men presented with significantly higher variation in PD response, whereas 12-15 h after dDAVP ODT intake women presented with a less predictable outcome, although all patients but one (female) have a prolonged PD effect. CONCLUSION: This study suggests the need for individualized dose titration rather than fixed dose regimens in NP patients with bothersome symptoms. Gender, body weight and results of nocturnal free water and sodium clearance need to be taken into account for more accurate individualized treatment to result in high response rates and low side effects.

Organic-aqueous crossover coating process for the desmopressin orally disintegrating microparticles.

The purpose of the present study was to prepare desmopressin orally disintegrating microparticles (ODMs) using organic-aqueous crossover coating process which featured an organic sub-coating followed by an aqueous active coating. Sucrose beads and hydroxypropyl cellulose (HPC) were used as inert cores and a coating material, respectively. Characterizations including size distribution analysis, in-vitro release studies and in-vitro disintegration studies were performed. A pharmacokinetic study of the ODMs was also conducted in eight beagle dogs. It was found that sucrose beads should be coated using organic solvents to preserve their original morphology. For the active coating, the aqueous coating solution should be used for drug stability. When sucrose beads were coated using organic-aqueous crossover coating process, double-layer ODMs with round shapes were produced with detectable impurities below limit of US Pharmacopeia. The median size of ODMs was 195.6 µm, which was considered small enough for a good mouthfeel. The ODMs dissolved in artificial saliva within 15 s because of hydrophilic materials including sucrose and HPC in the ODMs. Because of its fast-dissolving properties, 100% release of the drug was reached within 5 min. Pharmacokinetic parameters including Cmax and AUC24 indicated bioequivalence of the ODMs and the conventional immediate release tablets. Therefore, by using the organic-aqueous crossover coating process, double-layer ODMs were successively prepared with small size, round shapes and good drug stability.

Temporal delays and individual variation in antidiuretic response to desmopressin.

This study aimed to estimate the relationship between pharmacokinetics and the antidiuretic effect of desmopressin. In the investigator-blind, randomized, parallel group study, 5 dose groups and 1 placebo group, each consisting of 12 healthy, overhydrated, nonsmoking male subjects 18-55 yr of age were infused intravenously over 2 h with placebo or 30, 60, 125, 250, and 500 ng desmopressin in 50 ml of normal saline. Plasma desmopressin and urine osmolality rose by variable amounts during the infusions of 60, 125, 250, and 500 ng desmopressin. Plotting mean urine osmolality against the concurrent mean plasma desmopressin yielded a temporal delay between pharmacokinetic (PK) and -dynamic (PD) responses in all dose groups. Using simulation from the indirect-response model, assuming a constant (4 ng/ml) desmopressin concentration, this delay between PK and PD was estimated at 4 h (10th-90th percentile: 1.8-8.1). Within each group, however, there were large individual variations (2- to 10-fold) in the magnitude and duration of the antidiuretic effect. The antidiuretic effect of intravenous desmopressin in water-loaded healthy adults varies considerably due largely to factors other than individual differences in pharmacokinetics. The antidiuretic effect is time as well as dose dependent and may be self-amplifying. The most likely explanation for these findings is that the time required for a given level of plasma desmopressin to exert its maximum antidiuretic effect varies markedly from person to person due to individual differences in the kinetics of one or more of the intracellular mechanisms that promote the reabsorption of solute-free water by principal cells in renal collecting tubules.

Antidiuretic effect of desmopressin chimera agglomerates by nasal administration in rats.

In the present study, a nasal powder of the antidiuretic peptide desmopressin (DDAVP) formulated as chimera agglomerates was studied to improve drug bioavailability and provide a flexible drug product. Firstly, DDAVP was spray-dried along with mannitol and lecithin to produce primary microparticles capable of instantaneous dissolution in water. The chimera agglomerates were spontaneously formed by mechanically vibrating the microparticles on two stacked sieves. Agglomerate formation and strength were favored by the presence of lecithin. Drug content and dissolution rate remained unmodified after agglomeration. However, owing to the agglomerate larger size, powder flowability was greatly improved in comparison with the original microparticles, allowing accurate powder dosing into the nasal delivery device. DDAVP in vitro permeation across excised rabbit nasal mucosa from the agglomerates was significantly higher than that obtained from a commercial liquid nasal spray. In rats, intranasal DDAVP agglomerates allowed for efficient administration with almost 80% of the loaded powder emitted from the device into the animal nose. The administration of DDAVP agglomerates induced a significant reduction in urine production. Moreover, the antidiuretic effect of agglomerates did not significantly differ from the one induced by an intravenous injection of DDAVP at a ten-fold lower dose.

[Absorption of arginine-vasopressin and arginine-vasotocin in small intestine of the frog Rana temporaria].

Experiments in vitro demonstrated a partial absorption of arginine-vasopressin (AVP) in the frog small intestine. Dynamics and efficiency of the nonapeptide absorption are studied with use of hydroosmotic method of recording of the osmotic permeability of the frog urinary bladder epithelium and immunoenzyme analysis. In the process of absorption there were preserved intactness of the hormone cyclic structure and its physiological activity, like in the case of the arginine-vasotocin (AVT) absorption. The AVP absorption increased at its administration into the gut with inhibitor of proteases. By methods of immunoelectron and immunofluorescent microscopy with use of polyclonal antibody to AVP, location of the label to the hormone was shown in the enterocyte cytoplasm. Thus, there was obtained a morphological evidence for the AVP absorption and transepithelial transfer in the frog small intestine. These data enlarge the concept of the poorly studied properties of the absorbing epithelium of the vertebrate intestine with respect to absorption of intact molecules of polypeptides.

Reduced anti-diuretic response to desmopressin during wet nights in patients with monosymptomatic nocturnal enuresis.

OBJECTIVE: To investigate why not all children with monosymptomatic nocturnal enuresis (MNE) treated with desmopressin give an adequate response. MATERIALS AND METHODS: We included 114 children with MNE aged 5-15 years (9.8 ± 0.2 years) who experienced at least 1 wet night and more than 2 dry nights during desmopressin treatment. The patients made home recordings for 2 weeks as baseline and for 2-4 weeks of desmopressin titration. Nocturnal urine production during wet and dry nights, and maximum voided volumes (MVVs) were documented in all patients. RESULTS: Sixty-four patients were desmopressin non-responders, 29 were either partial responders or responders, while 21 patients were full responders. Desmopressin reduced nocturnal urine production dramatically during dry nights compared with pre-treatment wet nights. Nocturnal urine production during desmopressin treatment was significantly greater during wet nights compared to dry nights (243 ± 9.32 vs 176 ± 5.31 ml, P < 0.001). There was a highly significant correlation between individual nocturnal urine output and MVV, and dry nights were characterized by nocturnal urine output/MVV ratios well below 1.0. CONCLUSION: The anti-enuretic response to desmopressin seems to be dependent upon the degree of reduction in nocturnal urine production. Research on desmopressin bioavailability in children is needed.

Treatment of neurogenic diabetes insipidus.

Central or neurogenic diabetes insipidus results from a deficiency in antidiuretic hormone (ADH) or arginine-vasopressin (AVP). Treatment is based on replacement therapy with the hormone analog desmopressin (d-DAVP). d-DAVP can be administered subcutaneously to infants or patients with postoperative or posttraumatic brain injury being monitored for transient diabetes insipidus. Intranasal and oral forms are also available. The recently introduced lyophilisate, which melts under the tongue, has replaced the tablet form (recently withdrawn from the market in France) and provides better bioavailability. Irrespective of the mode of administration, it is usually the patient who finds the effective minimal dose necessary for a normal life, i.e. without excessive polyuria, particularly at night. Patient education is necessary to avoid the risk of water intoxication and hyponatremia.

Desmopressin duration of antidiuretic action in patients with central diabetes insipidus.

The key question answered by this study is whether it is possible to deliver a pharmacokinetic and pharmacodynamic duration of antidiuretic action long enough to ensure adequate antidiuresis with two daily administrations of desmopressin in patients with central diabetes insipidus (CDI). We studied the efficacy and safety of desmopressin i.v. in 13 CDI patients using two 3-way crossover designs, in the doses 30, 60, 125 ng, and 125, 250 and 500 ng. Duration of action, minimum output rate, max osmolality and average osmolality during action (AUC osmolality) were measured every 30 min for the first 2 h during the infusion, and then every hour or every second hour until the urine output rate was greater than 2 ml/kg/30 min. The duration of antidiuretic action was 4, 8 and 11 h, respectively, for 125, 250, and 500 ng, increasing from 250 to 500 ng but for the remaining secondary dynamic efficacy parameters no difference could be detected based on descriptive statistics between the doses 250 and 500 ng, indicating that the upper plateau region of the dose-response curve had been reached. All treatment emergent adverse events were classified as unrelated or unlikely related to trial medication. No serious adverse events occurred. Data on duration of action indicates that it is possible to achieve antidiuretic control with 500 ng i.v. corresponding to 160 µg orodispersible tablets twice daily in CDI patients. Today, the Minirin Melt label recommends the majority of CDI patients a dose of 60 to 120 µg t.i.d.

Oral lyophylizate formulation of desmopressin: superior pharmacodynamics compared to tablet due to low food interaction.

PURPOSE: Desmopressin is a standard treatment for monosymptomatic nocturnal enuresis. Different formulations are promoted as bioequivalent, although these claims are not supported by comparative pharmacodynamic data in children. Food interaction is known to influence the bioavailability of desmopressin. We compared the pharmacodynamics of the 2 most frequently used desmopressin formulations, tablet and lyophilizate, with a standardized meal, allowing extrapolation to clinical reality, where the interval between evening meal and medication intake is limited for school-age children. We hypothesized there would be a faster pharmacodynamic response, and greater concentrating and antidiuretic activity for the fast dissolving (melt) formulation compared to the tablet with simultaneous food intake. MATERIALS AND METHODS: Two tests were performed on separate days in identical standardized conditions, starting with a 15 ml/kg water load. After achieving maximal diluting capacity a standardized meal was administered, followed by desmopressin tablet (t test) or melt (M-test). Diuresis rate and urinary osmolality were measured hourly. Paired data from 4 girls and 15 boys with a mean age of 12.1 years were obtained. RESULTS: In the early response phase more than 25% of patients had a higher diuresis rate with tablet vs melt formulation, reaching statistical significance in the plateau phase (urine collected at hours 3 to 5, p <0.02) and in duration of action (urine collected at hours 5 to 8, p <0.005). For desmopressin melt smaller standard deviations in diuresis rate were remarkable. Concentrating capacity demonstrated no significant differences between formulations in the early response phase, in contrast to the plateau phase (p <0.036) and duration of action (p <0.001). CONCLUSIONS: With meal combination desmopressin melt formulation has a superior pharmacodynamic profile to tablet, making it more suitable for the younger age group with a limited interval between meal and drug administration.

Gender difference in antidiuretic response to desmopressin.

Increased age and female gender are well-known risk factors for the development of desmopressin-induced hyponatremia. However, little focus has been on exploring gender differences in the antidiuretic response to desmopressin. Based on an exploratory analysis from three clinical trials, we report a significant gender difference in the effects of desmopressin on nocturnal urine volume that could not be explained by pharmacokinetic differences. Mean desmopressin concentration profiles were tested for covariates, and age and gender were not statistically significant and only weight was significant for log(C(max)) (P = 0.0183) and borderline significant for log(AUC) (P = 0.0571). The decrease in nocturnal urine volume in nocturia patients treated with desmopressin over 28 days was significantly larger for women at the lower desmopressin melt doses of 10 and 25 µg than for men. The ED(50) for men was modeled to be 43.2 µg and 16.1 µg for women, with the ED(50) men/women estimated to be 2.7 (1.3-8.1 95% CI), corresponding to significantly higher sensitivity to desmopressin in women. An increasing incidence of hyponatremia with increasing dose was found, and at the highest dose level of 100 µg decreases in serum sodium were approximately twofold greater in women over 50 yr of age than in men. A new dose recommendation stratified by gender is suggested in the treatment of nocturia: for men, 50- to 100-µg melt is an efficacious and safe dose, while for women a dose of 25 µg melt is recommended as efficacious with no observed incidences of hyponatremia. Areas for further research are proposed to uncover pathophysiological mechanism(s) behind these gender differences.

Pharmacological characterization of FE 202158, a novel, potent, selective, and short-acting peptidic vasopressin V1a receptor full agonist for the treatment of vasodilatory hypotension.

FE 202158, ([Phe(2),Ile(3),Hgn(4),Orn(iPr)(8)]vasopressin, where Hgn is homoglutamine and iPr is isopropyl), a peptidic analog of the vasoconstrictor hormone [Arg(8)]vasopressin (AVP), was designed to be a potent, selective, and short-acting vasopressin type 1a receptor (V(1a)R) agonist. In functional reporter gene assays, FE 202158 was a potent and selective human V(1a)R agonist [EC(50) = 2.4 nM; selectivity ratio of 1:142:1107:440 versus human vasopressin type 1b receptor, vasopressin type 2 receptor (V(2)R), and oxytocin receptor, respectively] contrasting with AVP's lack of selectivity, especially versus the V(2)R (selectivity ratio of 1:18:0.2:92; human V(1a)R EC(50) = 0.24 nM). This activity and selectivity profile was confirmed in radioligand binding assays. FE 202158 was a potent vasoconstrictor in the isolated rat common iliac artery ex vivo (EC(50) = 3.6 nM versus 0.8 nM for AVP) and reduced rat ear skin blood flow after intravenous infusion in vivo (ED(50) = 4.0 versus 3.4 pmol/kg/min for AVP). The duration of its vasopressor effect by intravenous bolus in rats was as short as AVP at submaximally effective doses. FE 202158 had no V(2)R-mediated antidiuretic activity in rats by intravenous infusion at its ED(50) for reduction of ear skin blood flow, in contrast with the pronounced antidiuretic effect of AVP. Thus, FE 202158 seems suitable for treatment of conditions where V(1a)R activity is desirable but V(2)R activity is potentially deleterious, such as vasodilatory hypotension in septic shock. In addition to the desirable selectivity profile, its short-acting nature should allow dose titration with rapid onset and offset of action to optimize vasoconstriction efficacy and safety.