Pharmacokinetics, pharmacodynamics, long‐term efficacy and safety of oral 1‐deamino‐8‐d‐arginine vasopressin in adult patients with central diabetes insipidus

Abstract

1The pharmacokinetics and pharmacodynamics of intranasal (IN) and oral 1‐deamino‐8‐d‐arginine vasopressin (DDAVP) were compared in 10 Chinese adults with central diabetes insipidus previously controlled on IN DDAVP. This was followed by comparison of the acute pharmacodynamics of commonly used oral preparations (containing 100, 200 and 400 μg per tablet) and a 1 year prospective evaluation of the long‐term safety and efficacy of oral DDAVP. 2Following 20 μg IN and 200 μg orally, respective plasma DDAVP concentrations peaked after 45.6±7.3 and 93.3±3.3 (mean±s.e.mean) min, reaching 24.1±4.7 and 15.1±3.2 pmol l−1 and respective terminal half‐lives were 2.2±0.1 and 2.0±0.1 h. Based on the area under the concentration‐time‐curve, the bioequivalent IN/oral ratio was 1:16. 3As judged by changes in urine flow rate and osmolality after IN or oral (100, 200 or 400 μg) DDAVP, antidiuretic activity increased rapidly during the second hour and peaked at 4 h. The antidiuresis duration and magnitude correlated with the oral dose (P<0.001 and <0.05 respectively), and was least following 100 μg (P<0.01 vs 200 or 400 μg). Increasing the dose from 200 to 400 μg did not increase maximal antidiuretic activity significantly, but there was a trend towards a longer duration of action (P=0.076). 4During the 1‐year prospective study with oral DDAVP 300–600 μg per day in two to three doses, stable and satisfactory antidiuresis (comparable with that on previous IN therapy) was maintained; tablets were well‐tolerated and no side‐effect warranted drug withdrawal. 5These findings suggest that the 100 and 200 μg preparations of oral DDAVP are adequate for the long‐term control of central diabetes insipidus in our population, and that the 400 μg preparation may have a role if the frequency of administration is to be reduced.

Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study

“…In this study, some younger patients, for whom it was not easy to take desmopressin ODT in the daytime at school, were administered with a relatively high dose of desmopressin ODT bid, without negative effects. These data suggest that there is a need for individual dose titration as previously reported [8].…”

“…Nevertheless, there was wide variation of the intranasal desmopressin:ODT desmopressin ratios required to maintain similar levels of antidiuretic effect, ranging from 1:12 to 1:96. These data suggest that it is not possible to predict the required desmopressin ODT dose in a patient previously managed with intranasal desmopressin, and highlight the necessity of individ-other studies in CDI populations confirming that desmopressin in different formulations and bioequivalent strengths is an effective treatment for CDI [7,8,16,17]. This study supports the introduction of desmopressin ODT as the first-line therapy for antidiuretic control in patients with CDI.…”

“…No formal power calculation was performed to assess the sample size for this trial as the number of eligible patients is limited due to the rarity of CDI, with studies typically including 10-14 patients [7,12,8]. All primary and secondary endpoints were analysed based on the full analysis set (FAS), which included all exposed patients with at least one efficacy assessment after treatment.…”

“…In the subsequent 5-year continued administration, well-controlled urine output was observed in eight of the nine patients tested at daily maintenance doses of 0.2 mg to 0.6 mg, and no adverse drug reactions (ADRs) were reported. Though clinical data in Japanese patients are very limited, the dosage and administration of oral desmopressin used in the clinical study conducted by Fukuda et al [7] were equivalent to those used in overseas studies [8,9].…”

Comparison of incidence of hyponatremia between intranasal and oral desmopressin in patients with central diabetes insipidus

“…Patients with CDI are treated with desmopressin, an analogue of AVP, which is usually given twice or three times per day [7]. The concentration of desmopressin in blood reaches a peak soon after administration, and the antidiuretic action remains maximal for several hours [8][9][10][11]. Due to the pharmacokinetics/pharmacodynamics of desmopressin, its most frequent side effect in the treatment of CDI is hyponatremia [12,13].…”