Do Macrocyclic Peptide Drugs Interact with Bile Salts under Simulated Gastrointestinal Conditions?

Peptide drugs face several barriers to oral delivery, including enzymatic degradation in the gastrointestinal tract and low membrane permeability. Importantly, the direct interaction between various biorelevant colloids (i.e., bile salt micelles and bile salt-phospholipid mixed micelles) present in the aqueous gastrointestinal environment and peptide drug molecules has not been studied. In this work, we systematically characterized interactions between a water-soluble model peptide drug, octreotide, and a range of physiologically relevant bile salts in solution. Octreotide membrane flux in pure bile salt solutions and commercially available biorelevant media, i.e., fasted state simulated intestinal fluid (FaSSIF) and fed state simulated intestinal fluid (FeSSIF), was evaluated using a side-by-side diffusion cell equipped with a cellulose dialysis membrane. All seven micellar bile salt solutions as well as FaSSIF and FeSSIF decreased octreotide membrane flux, and dihydroxy bile salts were found to have a much larger effect than trihydroxy bile salts. An inverse relationship between octreotide membrane flux and pancreatic enzymatic stability was also observed; bile salt micelles and bile salt-phospholipid mixed micelles provided a protective effect toward enzymatic degradation and prolonged octreotide half-life in vitro. Diffusion ordered nuclear magnetic resonance (DOSY NMR) spectroscopy and dynamic light scattering (DLS) were used as complementary experimental techniques to confirm peptide-micelle interactions in solution. Experiments were also performed using desmopressin as a second model peptide drug; desmopressin interacted with bile salts in solution, albeit to a lower extent relative to octreotide. The findings described herein demonstrate that amphiphilic, water-soluble peptide drugs do interact with bile salts and phospholipids in solution, with an effect on peptide membrane flux and enzymatic stability. Correspondingly, oral peptide drug absorption and bioavailability may be impacted.

Population Pharmacokinetics of Clotting Factor Concentrates and Desmopressin in Hemophilia.

Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL-1) and some patients with moderate hemophilia (0.01-0.05 IU mL-1) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.

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.

Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration.

OBJECTIVE: Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability. METHODS: Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg-1, were included. A PK model was derived on the basis of the individual time profiles of VWF activity. Since no VWF was administered, the VWF dose was arbitrarily set to unity. Interpatient variability in bioavailability (F), volume of distribution (V), and clearance (Cl) was estimated. RESULTS: The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5-76), median predose VWF activity was 0.37 IU/mL (range: 0.06-1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04-4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While F increased with age, Cl was dependent on VWD type and sex. Inclusion resulted in a drop in interpatient variability in F and Cl of 81.7 to 60.5% and 92.8 to 76.5%, respectively. CONCLUSION: A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.

Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial.

Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Clinical trial registration www.clinicaltrials.gov NCT01623206.

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).

Desmopressin treatment combined with clotting factor VIII concentrates in patients with non-severe haemophilia A: protocol for a multicentre single-armed trial, the DAVID study.

INTRODUCTION: Haemophilia A is an inherited bleeding disorder characterised by factor VIII (FVIII) deficiency. In patients with non-severe haemophilia A, surgery and bleeding are the main indications for treatment with FVIII concentrate. A recent study reported that standard dosing frequently results in FVIII levels (FVIII:C) below or above FVIII target ranges, leading to respectively a bleeding risk or excessive costs. In addition, FVIII concentrate treatment carries a risk of development of neutralising antibodies. An alternative is desmopressin, which releases endogenous FVIII and von Willebrand factor. In most patients with non-severe haemophilia A, desmopressin alone is not enough to achieve FVIII target levels during surgery or bleeding. We hypothesise that combined pharmacokinetic (PK)-guided administration of desmopressin and FVIII concentrate may improve dosing accuracy and reduces FVIII concentrate consumption. METHODS AND ANALYSIS: In the DAVID study, 50 patients with non-severe haemophilia A (FVIII:C ≥0.01 IU/mL) with a bleeding episode or undergoing surgery will receive desmopressin and FVIII concentrate combination treatment. The necessary dose of FVIII concentrate to reach FVIII target levels after desmopressin administration will be calculated with a population PK model. The primary endpoint is the proportion of patients reaching FVIII target levels during the first 72 hours after start of the combination treatment. This approach was successfully tested in one pilot patient who received perioperative combination treatment. ETHICS AND DISSEMINATION: The DAVID study was approved by the medical ethics committee of the Erasmus MC. Results of the study will be communicated trough publication in international scientific journals and presentation at (inter)national conferences. TRIAL REGISTRATION NUMBER: NTR5383; Pre-results.

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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Pharmacokinetic Modelling to Predict FVIII:C Response to Desmopressin and Its Reproducibility in Nonsevere Haemophilia A Patients.

BACKGROUND: Nonsevere haemophilia A (HA) patients can be treated with desmopressin. Response of factor VIII activity (FVIII:C) differs between patients and is difficult to predict. OBJECTIVES: Our aims were to describe FVIII:C response after desmopressin and its reproducibility by population pharmacokinetic (PK) modelling. PATIENTS AND METHODS: Retrospective data of 128 nonsevere HA patients (age 7-75 years) receiving an intravenous or intranasal dose of desmopressin were used. PK modelling of FVIII:C was performed by nonlinear mixed effect modelling. Reproducibility of FVIII:C response was defined as less than 25% difference in peak FVIII:C between administrations. RESULTS: A total of 623 FVIII:C measurements from 142 desmopressin administrations were available; 14 patients had received two administrations at different occasions. The FVIII:C time profile was best described by a two-compartment model with first-order absorption and elimination. Interindividual variability of the estimated baseline FVIII:C, central volume of distribution and clearance were 37, 43 and 50%, respectively. The most recently measured FVIII:C (FVIII-recent) was significantly associated with FVIII:C response to desmopressin (p < 0.001). Desmopressin administration resulted in an absolute FVIII:C increase of 0.47 IU/mL (median, interquartile range: 0.32-0.65 IU/mL, n = 142). FVIII: C response was reproducible in 6 out of 14 patients receiving two desmopressin administrations. CONCLUSION: FVIII:C response to desmopressin in nonsevere HA patients was adequately described by a population PK model. Large variability in FVIII:C response was observed, which could only partially be explained by FVIII-recent. FVIII: C response was not reproducible in a small subset of patients. Therefore, monitoring FVIII:C around surgeries or bleeding might be considered. Research is needed to study this further.

Self-emulsifying peptide drug delivery systems: How to make them highly mucus permeating.

AIM: It was the aim of this study to evaluate the mucus permeating properties of self-emulsifying drug delivery systems (SEDDS) exhibiting different size and zeta potential. METHODS: Various SEDDS were prepared and characterized regarding droplet size, zeta potential and stability. Desmopressin was incorporated as model peptide drug and log P (SEDDS/water) was determined. Thereafter, mucus permeation studies with freshly isolated porcine mucus via Transwell method were performed. Moreover, the impact of water movement on mucus permeation of SEDDS was investigated. Different types of nanocarriers including nanoparticles and liposomes served as references. RESULTS: SEDDS exhibited an initial droplet size of 25.0 ±â€¯2.2, 49.5 ±â€¯4.6, 123.5 ±â€¯12.1, 226.2 ±â€¯93.4 and 502.9 ±â€¯93.7 nm and a zeta potential of +24.4 ±â€¯4.6, +10.6 ±â€¯2.0, 0.2 ±â€¯3.8, -8.2 ±â€¯3.4 and -35.1 ±â€¯2.7 mV. Log P was in the range of 1.29-2.09 and mucus permeation studies with these SEDDS revealed a clear correlation between droplet size and permeation rate. The smaller SEDDS were, the higher their mucus permeating properties were. Negatively charged SEDDS demonstrated a higher permeation rate than positively charged SEDDS. In comparison to liposomes and solid nanocarriers SEDDS exhibited up to 5-fold higher mucus permeating properties. CONCLUSION: Small droplet size and negative zeta potential of SEDDS could be identified as key parameters for their mucus permeating properties.

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.

[Desmopressin in the Treatment of Enuresis: Is Lyophilisate Superior to Tablets?] / Desmopressin in der Behandlung der Enuresis: Ist das Lyophilisat den Tabletten überlegen?

Background: Prognosis of MNE is good when adequate treatment starts in a timely manner. First-line treatment for monosymptomatic nocturnal enuresis (MNE) includes desmopressin (Grade A/Level 1 recommendation from the ICI). Missing or insufficient response to pharmacological treatment can be caused by incomplete compliance, but might also be associated with differences in bioavailability from the tablet form. This prospective, non-interventional study was designed to compare desmopressin tablets to the newer ,,melt'' formulation, also known as lyophilisate or orally disintegrating tablet (ODT). The primary endpoint of this study was the patients'/parents' acceptance; the secondary end point was a decrease in the number of wet nights. Materials and Methods: Each of the scheduled 100 participating doctors had to recruit two MNE candidates, one for each treatment group, with a planned total of 200 participants. At the end of the treatment period, treatment satisfaction, difficulties in taking the medication, forgotten doses and treatment success were reported. Results: In total, 134 patients were included (49 on tablet and 84 on melt). Difficulties in taking the medication and forgotten doses were significantly less with the melt than with the tablet formulation. Treatment satisfaction was better with melt. After the 3 months study, the number of wet nights was considerably reduced in both groups. With lyophilisate, a statistically significant greater reduction in wet nights was recorded as early as 2 weeks after starting the treatment. Conclusion: Desmopressin as orally disintegrating tablets is an effective treatment and is associated with improved patient compliance.

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.

Pharmacokinetics of desmopressin administered as tablet and oral lyophilisate formulation in children with monosymptomatic nocturnal enuresis.

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.

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.