Oral Lyophylizate Formulation of Desmopressin: Superior Pharmacodynamics Compared to Tablet Due to Low Food Interaction

Guchtenaere, Ann De; Herzeele, Charlotte Van; Raes, Ann; Dehoorne, Joke; Hoebeke, Piet; Laecke, Erik Van; Walle, Johan Vande

doi:10.1016/j.juro.2011.02.039

Cited by 56 publications

(26 citation statements)

References 21 publications

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“…Their bioequivalence at dose strengths of 200 µg and 120 µg, respectively, has been established in adults [10,11] but not in children. In a previous study, the lyophilisate has been shown to have a superior effect on diuresis in children, which was hypothesized to arise from a less pronounced food interaction [12]. DDAVP is to be taken in a fasted state before bedtime, which is challenging in young children, due to the short time between the last meal in the evening and bedtime.…”

Section: Introductionmentioning

confidence: 99%

Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children

et al. 2016

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Introduction: Desmopressin is used for nocturnal enuresis treatment 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 (22 children aged 6 to 16 yr and 25 children aged 6 to 13 yr) were analyzed using population pharmacokinetic modeling. A 1-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 desmopressin plasma concentrations adequately.Formulation and 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 relative bioavailability of 101%, compared to fed children. Body weight was included as a covariate on distribution volume, using a power function with exponent 0.402.Simulations suggest both the formulation and the food effect are clinically relevant. Conclusions:Bioequivalence data of two formulations of the same drug in adults, cannot be readily extrapolated to children. This is the first study in children suggesting that the two desmopressin formulations in children are not bioequivalent 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. Key points Population pharmacokinetic modeling was applied to pediatric desmopressin PK data and used to extract more information out of existing pediatric drug data, generate new information and improve the collection of future information. In this study it was found that the established bioequivalence of desmopressin in adults might be different in the pediatric population. A profound food effect was also quantified. In order to make solid conclusions regarding desmopressin efficacy in children, PK and PD data should be gathered simultaneously in a well-designed study, for which some design suggestions are presented in this paper. Abbreviations

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Section: Introductionmentioning

confidence: 99%

Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children

et al. 2016

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“…Stimulated by clinical observations that some patients with partial desmopressin response on the tablet benefitted from a switch to the melt, De Guchtenaere et al published data from a pharmacodynamic study in children with enuresis, demonstrating superior antidiuretic effect and concentrating capacity with the melt 120 μg compared with the bioequivalent 0.2 mg tablet [2]. The design of the study involved a single-dose administration and a standardised meal aimed to reflect more closely the clinical reality for young children with enuresis who are likely not to take the drug on an empty stomach.…”

Section: Introductionmentioning

confidence: 99%

Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis

et al. 2013

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Primary nocturnal enuresis is a prevalent childhood condition that can persist into adulthood. Desmopressin is an antidiuretic available as orally disintegrating lyophilisate (melt) or solid tablet. Recent findings suggesting different food interactions and clinical characteristics, including compliance, between desmopressin melt and tablet motivated a post hoc analysis of a previously reported randomised, crossover study. The efficacy of desmopressin melt compared with tablet was evaluated using the International Children’s Continence Society (ICCS) responder definitions. Compliance was further analysed using detailed criteria, and the association between efficacy and compliance was examined. In total, 221 patients aged 5–15 years, already receiving desmopressin tablets were randomised to the treatment sequence melt (120/240 μg)/tablet (0.2/0.4 mg) or tablet/melt in two consecutive 3-week periods. The probability of being a responder (partial or full) during either period was significantly more likely with desmopressin melt compared with tablet (odds ratio, 2.0; confidence intervals, 1.07–3.73; p = 0.03). There was no period effect on compliance in the tablet/melt sequence and no difference in the number of completely compliant patients in each formulation group; however, more patients were >75 % compliant in period 1 compared with period 2 in the melt/tablet sequence. Increased compliance was associated with greater reductions in the number of wet nights for both formulations. Conclusions: Desmopressin melt, compared with tablet, improves the probability of being a responder. Switching from tablet to melt formulation increased patient compliance. Increased compliance was associated with increased efficacy. Switching to desmopressin melt may benefit patients with suboptimal responses to desmopressin tablet.

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“…No water is required, leading to:reduced diuresisreduced fluid intake (as recommended to minimize hyponatremia risk and increase efficacy)increased convenience. Low food interaction is seen with the oral lyophilisate versus tablet [33], reducing difficulties posed by the short interval between the evening meal and bedtime for young children (see Recommendation 2). …”

Section: How To Maximize Desmopressin Success In the Right Patientmentioning

confidence: 99%

“…Low food interaction is seen with the oral lyophilisate versus tablet [33], reducing difficulties posed by the short interval between the evening meal and bedtime for young children (see Recommendation 2). …”

Section: How To Maximize Desmopressin Success In the Right Patientmentioning

confidence: 99%

“…The timing of medication administration is therefore likely, in reality, to fall short of recommended best practice, with food and desmopressin intake occurring at a similar time. Pharmacodynamic data show that the oral lyophilisate (120 μg) may be more effective and predictable than the bioequivalent 0.2 mg tablet when administered after a meal [33], with a significant increase in duration of action and indications of a shorter time to reach maximal antidiuresis and a higher concentrating capacity. Variability (standard deviation) in the diuresis rate was also lower with the oral lyophilisate, likely due to less interference with nutrition since the oral lyophilisate is believed to be reabsorbed by oral and/or oesophageal mucosa.…”

Section: How To Maximize Desmopressin Success In the Right Patientmentioning

confidence: 99%

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Optimizing response to desmopressin in patients with monosymptomatic nocturnal enuresis

et al. 2016

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Most patients with monosymptomatic nocturnal enuresis can be effectively treated with an enuresis alarm or antidiuretic therapy (desmopressin), depending on the pathophysiology of the condition in the individual patient. Desmopressin is first-line therapy for enuresis caused by nocturnal polyuria, an excessive urine output during the night. However, in a recent study, around one-third of patients thought to be resistant to desmopressin were subsequently treated effectively with desmopressin monotherapy in a specialist centre. The aim of this article is to review best practice in selecting patients for desmopressin treatment, as well as outline eight recommendations for maximizing the chances of treatment success in patients receiving desmopressin. The roles of formulation, dose, timing of administration, food and fluid intake, inter-individual variation in response, body weight, adherence, withdrawal strategies and combination therapies are discussed in light of the most recent research on desmopressin and enuresis. Possible reasons for suboptimal treatment response are explored and strategies to improve outcomes in patients for whom desmopressin is an appropriate therapy are presented. Through optimization of the treatment plan in primary and specialist care centres, the hope is that fewer patients with this distressing and often embarrassing condition will experience unnecessary delays in receiving appropriate care and achieving improvements.

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Oral Lyophylizate Formulation of Desmopressin: Superior Pharmacodynamics Compared to Tablet Due to Low Food Interaction

Abstract: 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.

Cited by 56 publications

References 21 publications

Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children

Effects of Food and Pharmaceutical Formulation on Desmopressin Pharmacokinetics in Children

Desmopressin melt improves response and compliance compared with tablet in treatment of primary monosymptomatic nocturnal enuresis

Optimizing response to desmopressin in patients with monosymptomatic nocturnal enuresis

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