DDAVP Melt for Primary Nocturnal Enuresis - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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DDAVP Melt for Primary Nocturnal Enuresis - Scientific Information

Manufacture: Ferring Pharmaceuticals
Country: Canada
Condition: Primary Nocturnal Enuresis
Class: Antidiuretic hormones
Form: Tablets
Ingredients: desmopressin, gelatin , mannitol, citric acid

Pharmaceutical Information

Drug Substance

Proprietary Name: Desmopressin Acetate
Chemical names: 1-Desamino-8-D-arginine vasopressin
acetate trihydrate

1-(3-mercaptopropanoic acid)-8-D-arginine
vasopressin monoacetate (salt) trihydrate
Molecular formula and molecular mass: C48H74N14017S2 (acetate trihydrate)
MW = 1183.2

C48H74N14017S2 (free base)
MW = 1069.2
Structural formula:
Physicochemical Properties : Desmopressin acetate is a white lyophilized powder which is soluble in water, methanol, ethanol, and acetic acid, and sparingly soluble in chloroform and ethyl acetate. An aqueous solution of 1 mg/mL at 24EC has a pH of 4.8.

Clinical Trials

Study demographics and trial design

Summary of patient demographics for clinical trials in the treatment of Primary Nocturnal Enuresis (PNE)
Study Trial Design Dosage, route of
administration and
duration
Number of
study subjects
Mean age
(range)
Gender
Study 5 Double-Blind,
Randomized,
Placebo-controlled,
Parallel Group
Study
DDAVP MELT
30, 60, 120, 240, 360, 480 ug
sublingually and placebo
sublingually
84 children 8.0 -9.4
(6-12 yrs)
64 Male
20 Female

A double-blind, randomized, placebo-controlled, parallel group study in children with PNE was conducted. The primary objective of this study was to determine the pharmacodynamic properties of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 µg) as DDAVP MELT in children with known PNE. The aim of this study was to identify doses that could provide duration of action corresponding to a typical length of night-time sleep in children with PNE.

The result of the study showed that urinary output fell markedly within the first hour after dosing for all patients in all desmopressin treatment groups; no such change was observed in the placebo group. Little difference was apparent between the creatinine-adjusted diuresis data (Figure 1) and the non-adjusted data. In the higher dose groups (240, 360 and 480 µg desmopressin) the same minimum level of urinary output was reached, suggesting that the maximum antidiuretic effect had been achieved.

Figure 1: Mean diuresis adjusted for creatinine over time following dosing

 

The change in mean osmolality over time showed onset of action within one hour following desmopressin dosing but no real change was apparent following placebo dosing (Figure 1). The urinary concentrating capacity of all six doses of desmopressin is indicated by the mean maximum osmolality achieved, which ranged from 515 to 957 mOsm/kg for the six different dose groups ( see Table 1), and generally occurred between 1 and 4 hours after dosing.

Figure 2: Mean osmolality over time following dosing

 

Table 1: Average osmolality during action, and maximum osmolality achieved; mean (SD)
Parameter DDAVP MELT (dose) Placebo
30 µg 60 µg 120 µg 240 µg 360 µg 480 µg
Number 12 12 11 12 13 12 12
Average
mOsm/kg during
action (SD)
277 (129) 464 (153) 576 (104) 671 (97) 680 (109) 647 (108) 50 (56)
Maximum
mOsm/kg (SD)
515 (239) 804 (188) 899 (83) 957 (105) 945 (119) 943 (125) 164 (150)

Threshold levels of 125, 200 and 400 mOsm/kg were used to determine duration of urinary concentrating action. In the placebo group, osmolality measurements never exceeded the highest atient; the intermediate 200 mOsm/kg threshold was exceeded by one patient only and the lowest (125 mOsm/kg) by five patients. At the lowest threshold, mean duration of action increased as the desmopressin dose increased, ranging from 3.6 hours following 30 µg desmopressin to 10.6 hours following the 480 µg dose (Table 2). A similar pattern was apparent for the two higher threshold levels.

Table 2: Duration of action of desmopressin using three osmolality thresholds (125, 200 and 400mOsm/kg)
  DDAVP MELT (dose) Placebo
(30 µg) (60 µg) (120 µg) (240 µg) (360 µg) (480 µg)
Number 12 12 11 12 13 12 12
125 mOsm/kg (hours)
Censored*
Mean (SD)
Median
Min – Max
3
3.6(2.1)
3.0
0.8–9.2
2
5.8(2.4)
5.4
2.2–10.9
4
8.1(1.9)
8.3
4.4–10.6
7
9.7(1.9)
10.8
6.2–11.6
10
10.2(1.0)
10.6
8.4–11.4
7
10.6(0.9)
10.5
8.9–12.3
2
0.6(1.3)
0.0
0.0–4.4
200 mOsm/kg (hours)
Censored*
Mean (SD)
Median
Min – Max/td>
0
2.4(1.7)
1.9
0.0–6.3
0
5.1(2.6)
4.6
1.8–10.9
3
7.5(2.1)
7.6
4.4–10.6
5
9.0(1.8)
9.8
5.6–10.8
5
9.2(1.6)
9.3
5.3–11.1
6
9.7(1.2)
9.6
7.7–11.3
0
0.1(0.2)
0.0
0.0–0.7
400 mOsm/kg (hours)
Censored*Mean (SD)MedianMin – Max 0
1.3(1.6)
1.1
0.0–4.4
0
4.0(2.6)
3.1
1.0–9.8
2
5.9(2.3)
6.3
1.9–10.5
3
8.2(2.3)
9.1
4.3–10.8
4
8.4(1.8)
8.4
4.2–10.3
4
8.6(1.4)
8.4
6.9–11.3
1
0.0(0.0)
0.0
0.0–0.0

* Number of patients with no ‘end’ of action; measurements were censored at the time the over hydration procedure was stopped.

The relationship between dose and duration of action is shown by the Kaplan-Meier plots in Figure 3. For all threshold levels of osmolality, particularly in the higher dose groups, the calculated duration of action is likely to be an underestimate. This is because for some children urine collections were stopped (censored) before urine osmolality had fallen below the threshold level. This may partially account for the apparent similarity between the higher dosage groups (240, 360 and 480 µg desmopressin).

Maximum urinary concentrating ability was thus observed at the doses of 120 µg and above, but this effect occurred over different time courses (Figure 2). Increasing the dose above 360 µg served to increase the duration of action which, for PNE children, would extend the period of antidiuresis into the daytime following the previous night’s dose. A dose range between 120 µg and 360 µg is therefore shown to be clinically relevant.

Figure 3: Relationship between duration of action and dose of desmopressin using osmolality thresholds of 125, 200 and 400 mOsm/kg, respectively

 

There was a marked fall in urinary output within 1 hour of dosing of DDAVP MELT and an increase in mean urinary osmolality in all hydrated children with PNE. The length of time for which this antidiuretic effect was observed increased as the dose increased. A clear dose-response relationship for the duration of urinary concentrating action was demonstrated at all three threshold levels of osmolality. For the lowest of the chosen thresholds (125 mOsm/kg) duration of action ranged from about 3 hours to 10.5 hours, according to dose. It is likely that the actual duration of action was somewhat longer than this for the higher doses of desmopressin (240, 360 and 480 µg) as urinary collections ceased for about half the children in these groups before the osmolality had returned to below this threshold. The data clearly indicate that if higher doses are administered in the evening there is a need to follow the diuresis rate the next morning to avoid risk of water intoxication.

The predictable fast-reaching maximum concentrating ability observed in this study suggests a constant antidiuretic response for DDAVP MELT. After 60 minutes, a mean maximum osmolality above 800 mOsm/kg was achieved following all doses of desmopressin, with the exception of the lowest dose (30 µg). Even with the 30 µg dose the maximum effect was observed after 60 minutes, but maximum concentrating capacity was not obtained. This demonstrates that the time to peak activity is very predictable, even at low doses (± 60 min).

Fifty percent of the patients receiving the 60 µg dose had a maximum osmolality above 800 mOsm/kg. This is close to the maximum urinary concentrating capacity in children, and suggests that 60 µg desmopressin as DDAVP MELT could be an adequate dose in some children. The required duration of maximum activity versus speed of maximum diluting capacity is an important consideration, as this balance will determine the maximal effectiveness and the risk of side effects during the day.

Approximately 50% of enuretic episodes in children occur during the early hours of the night. A pharmacological action lasting for three hours may be sufficient for some patients. If a longer duration of action is needed, doses of 120 µg desmopressin or greater would be required. Even at the highest threshold, the 120 µg dose maintained a urinary concentrating effect for approximately six hours. It therefore appears to be possible, even in a prediluted child, to control diuresis for 7–11 hours, a period similar to the sleeping time for children, with DDAVP MELT at a dose in the region of 120–360 µg. In clinical practice, children should be advised to restrict fluid intake one hour before taking DDAVP MELT.

The data suggest that a 60 µg dose could be appropriate for some children. However for bioactivity throughout the night, 120 µg is preferable. For a few children treated with 120 µg the urinary concentrating effect did not last for 11 hours, suggesting that the dose of desmopressin was suboptimal. In these patients a dose increase to 240 or 360 μg ensures antidiuresis will be obtained for the whole night.

The apparent similarity between the three highest doses of desmopressin in terms of duration of action, minimum level of urinary output and maximum osmolality following dosing suggests that the maximum dose response had been achieved. Therefore, a dose in excess of 360 µg desmopressin may not be necessary. It would also reduce the risk of adverse events, as all but one adverse event reported in this study occurred in the 480 µg dose group. In general, DDAVP

MELT was well tolerated with the type of adverse events being the same as has been reported for desmopressin tablets.

This study revealed that DDAVP MELT causes a marked fall in urinary output in hydrated patients with PNE. Using a small dosage range (120–360 µg) it is likely that diuresis can be controlled for a period corresponding to a night’s sleep (7–11 hours) for many of the PNE patients.

Toxicology

Acute Toxicity

The i.v. acute toxicity of desmopressin acetate is very low. Mice tolerate i.v. doses of 2 mg/kg (see table below). At doses of 30 µg/kg in rats and 50 µg/kg in rabbits, only transient changes in clinical behaviour were observed. Intravenous doses up to 24 µg/kg in dogs did not produce any cardiovascular changes.

Acute Toxicity of Desmopressin Acetate
Species Number LD50 Dose Route
Mice 10, both sexes 2 mg/kg i.v.
Rats 12, both sexes 30 μg/kg i.v.
Rabbits 6, both sexes 50 μg/kg i.v.
Dogs 5, males 24 μg/kg i.v.

Subacute Toxicity

Results from 14-day studies show that the drug given intravenously to rats at

18 µg/kg/day and to rabbits at 6 µg/kg/day caused no biologically significant changes in hematological and clinical chemistry parameters. Post-mortem examinations did not reveal any abnormalities.

Rats which received 5 mg/kg/day subcutaneously for 3 weeks did not show any significant changes in weight, blood count, or organ changes.

Chronic Toxicity

Subcutaneous Administration

Rat Studies

In a controlled 8-week experiment, 20 rats received 2 µg/kg/day desmopressin acetate subcutaneously. No increase in blood glucose or morphological or histological pancreatic changes occurred.

Rats (20 per group) which received doses of 5, 50 and 500 ng/kg/day, for six months did not show any significant changes in weight, blood values, or levels of transaminases. The weight of heart, lungs and kidneys decreased in female animals in the lower dose groups but not in the higher ones. In the male animals a decrease in non-esterified fatty acids was noted.

Dog Studies

Dogs (3 per group) which received subcutaneous doses of 10 and 100 ng/kg/day for 6 months did not show any significant changes in comparison with control groups in blood sugar or transaminases and did not show histological or morphological organ changes.

Oral Administration

Rat Studies

Oral administration of desmopressin to rats (20 male and 20 females per group dosed at 25, 75 and 200 µg/kg/day) did not reveal any clinical findings related to desmopressin. Treated male and female rats were comparable to controls with respect to food consumption, body weight gain and water consumption. There were no drug-induced ocular abnormalities.

A dosage-related reduction was seen in levels of total circulating white blood cells, attributable to reduced neutrophil and lymphocyte counts in treated females, when compared with controls, at the week 13 and 26 investigations. Treated males were not affected.

Reduced plasma Factor VIII levels were seen in treated females at week 14 and treated males at week 25 in comparison with controls.

The terminal studies revealed no morphological or histological changes related to treatment with desmopressin.

Dog Studies

When desmopressin was given orally to dogs (4 males and 4 females per group, at 0, 25, 75 and 200 µg/kg/day) all animals survived the 26-week period and no clinical signs were observed that were related to treatment. There were no adverse effects on body weight, food and water consumption and no ocular abnormalities. Hematological investigations revealed no treatment-related findings.

During weeks 6, 13 and 26 serum total protein concentrations of treated animals were increased due to an increase in the globulin fraction. However, there were no changes from the pre-dose values in males at 200 µg/kg/day after 13 and 26 weeks treatment and males at 75 µg/kg/day after 26 weeks treatment.

No organ morphological or histological changes were seen on autopsy which could be related to treatment with desmopressin.

Reproduction Studies

Subcutaneous Administration

Rat Studies

In a teratogenicity study in Wistar rats, neither teratologic nor embryotoxic effects were observed in 369 foetuses from 40 females dosed with up to 50 ng/kg/day desmopressin acetate subcutaneously during day 1 to day 20 of gestation.

Rabbit Studies

In a study of 78 Dutch belted rabbits which received subcutaneous doses of desmopressin acetate up to 10 µg/kg/day during the sixth and eighteenth day of pregnancy, neither teratogenic nor embryotoxic effects were observed in 296 fetuses. Weaning was unaffected.

Intravenous Administration

Rat Studies

A teratology study was performed in rats. Groups of 30 pregnant Slc:Wistar rats were treated daily from day 7 to day 17 of gestation by i.v. administration of DDAVP at dosage levels of 9.47, 47.4 and 238 mg desmopressin/kg/day. A control group received the vehicle, physiological saline. Twenty females in each group were killed on day 20 of gestation to allow fetal examinations; the remaining 10 females were allowed to litter to determine any postnatal effects that might be attributable to prenatal treatment. There were no effects of treatment on the dams, and fetal survival, growth and morphology were also unaffected. Postnatal offspring survival, growth, development, behaviour and reproductive performance also showed no effects of prenatal exposure to desmopressin.