The Experts below are selected from a list of 474 Experts worldwide ranked by ideXlab platform
Johan Vande Walle - One of the best experts on this subject based on the ideXlab platform.
-
Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review
Pediatric Drugs, 2020Co-Authors: Elke Gasthuys, Lien Dossche, Jens Peter Norgaard, Robin Michelet, Jan Van Bocxlaer, Mathias Devreese, Siska Croubels, An Vermeulen, Johan Vande WalleAbstract:Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication—nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration–time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.
-
effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children
Clinical Pharmacokinectics, 2016Co-Authors: Robin Michelet, Lien Dossche, Pauline De Bruyne, Pieter Colin, Koen Boussery, Jan Van Bocxlaer, Johan Vande Walle, An VermeulenAbstract: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.
-
pharmacokinetics of desmopressin administered as tablet and oral Lyophilisate formulation in children with monosymptomatic nocturnal enuresis
European Journal of Pediatrics, 2014Co-Authors: Pauline De Bruyne, Jo Dehoorne, Piet Hoebeke, Charlotte Van Herzeele, A De Guchtenaere, Ann Raes, Erik Van Laecke, Johan Vande WalleAbstract:Desmopressin 120 μg oral Lyophilisate and 200 μg tablet are considered bioequivalent, based on extrapolation of studies in a limited number of adults and on one dose-finding study of desmopressin oral Lyophilisate in children. However, no comparative pharmacokinetic study in children was executed confirming this statement. No data are available on the influence of food intake on the bioavailability of desmopressin tablet in a pediatric setting, although studies in adults have documented that food intake results in a significantly lower desmopressin plasma concentration. In this study, we analyzed plasma concentrations of desmopressin oral Lyophilisate and tablet with concomitant food intake. Twenty-three children with monosymptomatic nocturnal enuresis (mean age, 12.7 years) were recruited. Two tests were performed on two separate days in identical conditions with a standardized food and fluid intake. Desmopressin was administered as desmopressin tablet or desmopressin oral Lyophilisate immediately after a meal. Desmopressin plasma concentration was measured at 1 h, 2 h, and 6 h postdosing. No significant difference in plasma concentration of 120 μg desmopressin oral Lyophilisate and 200 μg tablet was demonstrated, even with concomitant food intake. A significant difference in variability was found, identifying a smaller variance for desmopressin oral Lyophilisate plasma concentrations at all time points. This study demonstrates comparable plasma levels for desmopressin oral Lyophilisate, despite the lower dose. The dosage for desmopressin oral Lyophilisate is more predictable due to the significantly smaller variance. Therefore, desmopressin oral Lyophilisate seems more suitable, especially in the younger age group for which time interval between dinner and drug administration is limited.
-
pharmacokinetics of desmopressin administrated as an oral Lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults
The Journal of Clinical Pharmacology, 2006Co-Authors: Ole Osterberg, Jens Peter Norgaard, Johan Vande Walle, Radojka M Savic, Mats O Karlsson, Ulrika S H Simonsson, Henrik AgersoAbstract:The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1-compartment model with first-order absorption and first-order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag-time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag-time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.
-
a new fast melting oral formulation of desmopressin a pharmacodynamic study in children with primary nocturnal enuresis
BJUI, 2006Co-Authors: Johan Vande Walle, Piet Hoebeke, Guy G A Bogaert, Sven Mattsson, Thierry Schurmans, Veerle V Deboe, Jens Peter NorgaardAbstract:Objective To determine the pharmacodynamic properties of a new oral Lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 mu g) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night-time sleep in children with PNE; additional objectives were to determine the safety and tolerability of desmopressin in this population. Patients and Methods Children with PNE (mean three or more wet nights/week), aged 6-12 years, were randomized into a double-blind, placebo-controlled study. An overhydration technique was used before dosing to suppress endogenous vasopressin production and thereby ensure that any antidiuresis could be attributed to treatment. Dosing with desmopressin or placebo occurred when urinary production was > 0.13 mL/min/kg. Urinary volume, osmolality and duration of urinary-concentrating action (above three threshold levels: 125, 200 and 400 mOsm/kg) were determined as endpoints. Results All 72 participants receiving desmopressin had a pharmacodynamic response to the drug, while there was no change in urinary output in the 12 placebo-treated patients. There was a clear relationship between desmopressin dose and duration of action and osmolality during action, although the three highest-dose groups had similar results. The mean duration of action of desmopressin at the lowest osmolality threshold level was 3.6-10.6 h, according to dose; for the highest threshold, the values were 1.3-8.6 h. Conclusion Desmopressin, as the oral Lyophilisate, causes a marked decrease in urinary output in hydrated children with PNE. A small dose range (120-240 mu g) is likely to control diuresis for a period corresponding to a night's sleep (7-11 h) in most children with PNE. However, some patients might require a higher dose to obtain antidiuresis for the complete night. (Less)
Jens Peter Norgaard - One of the best experts on this subject based on the ideXlab platform.
-
Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review
Pediatric Drugs, 2020Co-Authors: Elke Gasthuys, Lien Dossche, Jens Peter Norgaard, Robin Michelet, Jan Van Bocxlaer, Mathias Devreese, Siska Croubels, An Vermeulen, Johan Vande WalleAbstract:Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication—nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration–time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.
-
pharmacokinetics of desmopressin administrated as an oral Lyophilisate dosage form in children with primary nocturnal enuresis and healthy adults
The Journal of Clinical Pharmacology, 2006Co-Authors: Ole Osterberg, Jens Peter Norgaard, Johan Vande Walle, Radojka M Savic, Mats O Karlsson, Ulrika S H Simonsson, Henrik AgersoAbstract:The population pharmacokinetics of desmopressin in children with nocturnal enuresis and in healthy adults were compared using a 1-compartment model with first-order absorption and first-order elimination. In addition, the model consisted of a number of transit compartments before absorption to describe a lag-time. The model gave an adequate description of adult as well as children data and provided a statistically significant better fit to data than a standard lag-time model. The main difference in the pharmacokinetics between children and adults was the absorption delay. The pharmacokinetic difference was minor and presumably of no clinical relevance.
-
a new fast melting oral formulation of desmopressin a pharmacodynamic study in children with primary nocturnal enuresis
BJUI, 2006Co-Authors: Johan Vande Walle, Piet Hoebeke, Guy G A Bogaert, Sven Mattsson, Thierry Schurmans, Veerle V Deboe, Jens Peter NorgaardAbstract:Objective To determine the pharmacodynamic properties of a new oral Lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 mu g) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night-time sleep in children with PNE; additional objectives were to determine the safety and tolerability of desmopressin in this population. Patients and Methods Children with PNE (mean three or more wet nights/week), aged 6-12 years, were randomized into a double-blind, placebo-controlled study. An overhydration technique was used before dosing to suppress endogenous vasopressin production and thereby ensure that any antidiuresis could be attributed to treatment. Dosing with desmopressin or placebo occurred when urinary production was > 0.13 mL/min/kg. Urinary volume, osmolality and duration of urinary-concentrating action (above three threshold levels: 125, 200 and 400 mOsm/kg) were determined as endpoints. Results All 72 participants receiving desmopressin had a pharmacodynamic response to the drug, while there was no change in urinary output in the 12 placebo-treated patients. There was a clear relationship between desmopressin dose and duration of action and osmolality during action, although the three highest-dose groups had similar results. The mean duration of action of desmopressin at the lowest osmolality threshold level was 3.6-10.6 h, according to dose; for the highest threshold, the values were 1.3-8.6 h. Conclusion Desmopressin, as the oral Lyophilisate, causes a marked decrease in urinary output in hydrated children with PNE. A small dose range (120-240 mu g) is likely to control diuresis for a period corresponding to a night's sleep (7-11 h) in most children with PNE. However, some patients might require a higher dose to obtain antidiuresis for the complete night. (Less)
Piet Hoebeke - One of the best experts on this subject based on the ideXlab platform.
-
pharmacokinetics of desmopressin administered as tablet and oral Lyophilisate formulation in children with monosymptomatic nocturnal enuresis
European Journal of Pediatrics, 2014Co-Authors: Pauline De Bruyne, Jo Dehoorne, Piet Hoebeke, Charlotte Van Herzeele, A De Guchtenaere, Ann Raes, Erik Van Laecke, Johan Vande WalleAbstract:Desmopressin 120 μg oral Lyophilisate and 200 μg tablet are considered bioequivalent, based on extrapolation of studies in a limited number of adults and on one dose-finding study of desmopressin oral Lyophilisate in children. However, no comparative pharmacokinetic study in children was executed confirming this statement. No data are available on the influence of food intake on the bioavailability of desmopressin tablet in a pediatric setting, although studies in adults have documented that food intake results in a significantly lower desmopressin plasma concentration. In this study, we analyzed plasma concentrations of desmopressin oral Lyophilisate and tablet with concomitant food intake. Twenty-three children with monosymptomatic nocturnal enuresis (mean age, 12.7 years) were recruited. Two tests were performed on two separate days in identical conditions with a standardized food and fluid intake. Desmopressin was administered as desmopressin tablet or desmopressin oral Lyophilisate immediately after a meal. Desmopressin plasma concentration was measured at 1 h, 2 h, and 6 h postdosing. No significant difference in plasma concentration of 120 μg desmopressin oral Lyophilisate and 200 μg tablet was demonstrated, even with concomitant food intake. A significant difference in variability was found, identifying a smaller variance for desmopressin oral Lyophilisate plasma concentrations at all time points. This study demonstrates comparable plasma levels for desmopressin oral Lyophilisate, despite the lower dose. The dosage for desmopressin oral Lyophilisate is more predictable due to the significantly smaller variance. Therefore, desmopressin oral Lyophilisate seems more suitable, especially in the younger age group for which time interval between dinner and drug administration is limited.
-
oral lyophylizate formulation of desmopressin superior pharmacodynamics compared to tablet due to low food interaction
The Journal of Urology, 2011Co-Authors: A De Guchtenaere, Jo Dehoorne, Piet Hoebeke, Charlotte Van Herzeele, Ann Raes, Erik Van Laecke, Vande J WalleAbstract: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...
-
a new fast melting oral formulation of desmopressin a pharmacodynamic study in children with primary nocturnal enuresis
BJUI, 2006Co-Authors: Johan Vande Walle, Piet Hoebeke, Guy G A Bogaert, Sven Mattsson, Thierry Schurmans, Veerle V Deboe, Jens Peter NorgaardAbstract:Objective To determine the pharmacodynamic properties of a new oral Lyophilisate formulation of desmopressin (in single doses of 30, 60, 120, 240, 360 or 480 mu g) in children with known primary nocturnal enuresis (PNE) and thus identify those dosages that could provide a duration of action corresponding to a typical length of night-time sleep in children with PNE; additional objectives were to determine the safety and tolerability of desmopressin in this population. Patients and Methods Children with PNE (mean three or more wet nights/week), aged 6-12 years, were randomized into a double-blind, placebo-controlled study. An overhydration technique was used before dosing to suppress endogenous vasopressin production and thereby ensure that any antidiuresis could be attributed to treatment. Dosing with desmopressin or placebo occurred when urinary production was > 0.13 mL/min/kg. Urinary volume, osmolality and duration of urinary-concentrating action (above three threshold levels: 125, 200 and 400 mOsm/kg) were determined as endpoints. Results All 72 participants receiving desmopressin had a pharmacodynamic response to the drug, while there was no change in urinary output in the 12 placebo-treated patients. There was a clear relationship between desmopressin dose and duration of action and osmolality during action, although the three highest-dose groups had similar results. The mean duration of action of desmopressin at the lowest osmolality threshold level was 3.6-10.6 h, according to dose; for the highest threshold, the values were 1.3-8.6 h. Conclusion Desmopressin, as the oral Lyophilisate, causes a marked decrease in urinary output in hydrated children with PNE. A small dose range (120-240 mu g) is likely to control diuresis for a period corresponding to a night's sleep (7-11 h) in most children with PNE. However, some patients might require a higher dose to obtain antidiuresis for the complete night. (Less)
Diestelhorst M - One of the best experts on this subject based on the ideXlab platform.
-
Bioavailability of fluorescein from a new drug delivery system in human eyes
Copyright 2004 British Journal of Ophthalmology, 2004Co-Authors: Steinfeld A, Lux A, Maier S, Süverkrüp R, Diestelhorst MAbstract:Aim: To assess the ocular bioavailability of fluorescein from a novel drug delivery system compared with one single preservative free eye drop. Methods: Part A: In a randomised study 10 volunteers applied the Lyophilisate to one eye and a conventional fluorescein eye drop to the fellow eye. Fluorophotometry was performed before and every 2 minutes up to 30 minutes after application in the cornea and anterior chamber. Part B: Another 10 volunteers applied each form of the application. Fluorophotometry was performed before, +2 minutes, and at +8, +10, +12 hours. The dose corresponding to a single fluorescein dose of the Lyophilisate was 68 l μg fluorescein SE 0.17%. Results: Part A: During the first 30 minutes after administration of the preservative free eye drop of 40 μg the corneal and anterior chamber concentration means were up to 16 times higher in eyes treated with the Lyophilisate. Part B: 8–12 hours after application the mean fluorescein concentration in the cornea of the Lyophilisate group was two times higher than at baseline. Eyes treated with eye drops had baseline values at +8, +10 and +12 hours. Conclusion: A significantly better bioavailability was achieved in human eyes by using Lyophilisate compared with the same dose from a conventional eye drop. Lyophilisates are a favourable alternative to conventional eye drops since they have no preservatives, higher long term stability, no pH adjustment, and easy handling
-
A comparative bioavailability study of three conventional eye drops versus a single Lyophilisate
Copyright 2003 British Journal of Ophthalmology, 2003Co-Authors: Lux A, Maier S, Süverkrüp R, Dinslage S, Diestelhorst MAbstract:Aim: To study the ocular bioavailability of a triple dose, single application of sodium fluorescein to the human anterior segment from a novel drug delivery device. Methods: In a randomised, open label study 22 healthy volunteers applied a single Lyophilisate to one eye (+1 minute) and three conventional eye drops (+1, 16, 31 minutes) of fluorescein ophthalmic solution to the fellow eye. The fluorescein dose of the Lyophilisate was 204 mg corresponding to three conventional, preservative-free eye drops of 40 ml fluorescein SE Thilo 0.17% (68 μg each) (Alcon). Fluorophotometry was performed (Fluorotron Master II Ocumetrics, USA) before and +15, 30, 45, 60, 120, 180, 240, 300, 360, 420 minutes after application. The fluorescein concentrations of the corneal stroma and mid-anterior chamber were analysed by paired t test. Results: Cornea and anterior chamber mean values (ng/ml) were significantly higher (p
-
Lyophilisates for drug delivery in ophthalmology: pharmacokinetics of fluorescein in the human anterior segment
Copyright 2002 British Journal of Ophthalmology, 2002Co-Authors: Dinslage S, Diestelhorst M, Weichselbaum A, Süverkrüp RAbstract:Aims: To assess the ocular bioavailability of fluorescein from a novel water free, freeze dried ophthalmic drug delivery system compared to conventional preservative-free fluorescein eye drops. Methods: Sodium fluorescein 0.17% was dissolved in an aqueous solution of hydroxypropylmethyl cellulose 1.0% (HPMC), deposited on sterilised flexible hydrophobic poly(tetrafluoroethylene) (PTFE) carrier strips and freeze dried under aseptic conditions. The fluorescein dose of the Lyophilisate was 68 μg, corresponding to a single conventional drop of 40 μl fluorescein 0.17% solution. In a randomised, open label study 12 healthy volunteers applied the lyophilised fluorescein to one eye and one drop of conventional fluorescein ophthalmic solution to the fellow eye. Fluorophotometry measurements of fluorescein concentrations in the anterior segment were performed with the Fluorotron Master II (Ocumetrics, USA) before and +15, 30, 45, 60, 120, and 180 minutes after application. Results: At all times anterior chamber fluorescein concentration was greater in the lyophysilate treated eye than the solution treated eye. The magnitude of this difference ranged from 2–5.3 times and was statistically significant. Conclusion: The greater intraocular bioavailability of fluorescein from the Lyophilisate relative to the solution suggests that it may be a useful method for delivering substances to the eye
An Vermeulen - One of the best experts on this subject based on the ideXlab platform.
-
Desmopressin oral Lyophilisate in young children : new insights in pharmacokinetics and pharmacodynamics
'BMJ', 2021Co-Authors: Dossche Lien, An Vermeulen, De Bruyne Pauline, Van Herzeele Charlotte, Michelet Robin, Gasthuys Elke, Rittig Søren, Vande Walle JohanAbstract: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
-
Pediatric Pharmacology of Desmopressin in Children with Enuresis: A Comprehensive Review
Pediatric Drugs, 2020Co-Authors: Elke Gasthuys, Lien Dossche, Jens Peter Norgaard, Robin Michelet, Jan Van Bocxlaer, Mathias Devreese, Siska Croubels, An Vermeulen, Johan Vande WalleAbstract:Desmopressin is a synthetic analogue of the natural antidiuretic hormone arginine vasopressin. Over the years, it has been clinically used to manage nocturnal polyuria in children with enuresis. Various pharmaceutical formulations of desmopressin have been commercialized for this indication—nasal spray, nasal drops, oral tablet and oral lyophilizate. Despite the fact that desmopressin is a frequently prescribed drug in children, its use and posology is based on limited pediatric data. This review provides an overview of the current pediatric pharmacological data related to the different desmopressin formulations, including their pharmacokinetics, pharmacodynamics and adverse events. Regarding the pharmacokinetics, a profound food effect on the oral bioavailability was demonstrated as well as different plasma concentration–time profiles (double absorption peak) of the desmopressin lyophilizate between adults and children. Literature about maturational differences in distribution, metabolism and excretion of desmopressin is rather limited. Regarding the pharmacodynamics, formulation/dose/food effect and predictors of response were evaluated. The lyophilizate is the preferred formulation, but the claimed bioequivalence in adults (200 µg tablet and 120 µg lyophilizate), could not be readily extrapolated to children. Prescribing the standard flat-dose regimen to the entire pediatric population might be insufficient to attain response to desmopressin treatment, whereby dosing schemes based on age and weight were proposed. Moreover, response to desmopressin is variable, whereby complete-, partial- and non-responders are reported. Different reasons were enumerated that might explain the difference in response rate to desmopressin observed: different pathophysiological mechanisms, bladder capacity and other predictive factors (i.e. breast feeding, familial history, compliance, sex, etc.). Also, the relapse rate of desmopressin treatment was high, rendering it necessary to use a pragmatic approach for the treatment of enuresis, whereby careful consideration of the position of desmopressin within this treatment is required. Regarding the safety of the different desmopressin formulations, the use of desmopressin was generally considered safe, but additional measures should be taken to prevent severe hyponatremia. To conclude the review, to date, major knowledge gaps in pediatric pharmacological aspects of the different desmopressin formulations still remain. Additional information should be collected about the clinical relevance of the double absorption peak, the food effect, the bioequivalence/therapeutic equivalence, the pediatric adapted dosing regimens, the study endpoints and the difference between performing studies at daytime or at nighttime. To fill in these gaps, additional well designed pharmacokinetic and pharmacodynamic studies in children should be performed.
-
An integrated paediatric population PK/PD analysis of dDAVP : how do PK differences translate to clinical outcomes?
'Springer Science and Business Media LLC', 2020Co-Authors: Michelet Robin, De Bruyne Pauline, Van Herzeele Charlotte, Vande Walle Johan, Dossche Lien, Gasthuys Elke, Van Bocxlaer Jan, An VermeulenAbstract: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 mu g 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
-
effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children
Clinical Pharmacokinectics, 2016Co-Authors: Robin Michelet, Lien Dossche, Pauline De Bruyne, Pieter Colin, Koen Boussery, Jan Van Bocxlaer, Johan Vande Walle, An VermeulenAbstract: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.
-
Effects of food and pharmaceutical formulation on desmopressin pharmacokinetics in children
'Springer Science and Business Media LLC', 2016Co-Authors: Michelet Robin, De Bruyne Pauline, Vande Walle Johan, Dossche Lien, Colin Pieter, Boussery Koen, Van Bocxlaer Jan, An VermeulenAbstract: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
