Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU-MOMs sub-registries.

Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels between 120 and 360 µmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk-benefit ratio when used during pregnancy. Data from the maternal sub-registries-KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU-MOMs sub-registry)-were collected to assess the long-term safety and efficacy of sapropterin in pregnant women in a real-life setting. Pregnancy and infant outcomes, and the safety of sapropterin were assessed. Final data from 79 pregnancies in 57 women with PKU are reported. Sapropterin dose was fairly constant before and during pregnancy, with blood Phe levels maintained in the recommended target range during the majority (82%) of pregnancies. Most pregnancies were carried to term, and the majority of liveborn infants were reported as 'normal' at birth. Few adverse and serious adverse events were considered related to sapropterin, with these occurring in participants with high blood Phe levels. This report represents the largest population of pregnant women with PKU exposed to sapropterin. Results demonstrate that exposure to sapropterin during pregnancy was well-tolerated and facilitated maintenance of blood Phe levels within the target range, resulting in normal delivery. This critical real-world data may facilitate physicians and patients to make informed treatment decisions about using sapropterin in pregnant women with PKU and in women of childbearing age with PKU who are responsive to sapropterin.

RETRACTED: Wiesinger et al. An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis. Pharmaceutics 2023, 15, 1565.

The journal retracts the article, An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis [...].

An artificial intelligence-based approach for identifying rare disease patients using retrospective electronic health records applied for Pompe disease.

Objective: We retrospectively screened 350,116 electronic health records (EHRs) to identify suspected patients for Pompe disease. Using these suspected patients, we then describe their phenotypical characteristics and estimate the prevalence in the respective population covered by the EHRs. Methods: We applied Symptoma's Artificial Intelligence-based approach for identifying rare disease patients to retrospective anonymized EHRs provided by the "University Hospital Salzburg" clinic group. Within 1 month, the AI screened 350,116 EHRs reaching back 15 years from five hospitals, and 104 patients were flagged as probable for Pompe disease. Flagged patients were manually reviewed and assessed by generalist and specialist physicians for their likelihood for Pompe disease, from which the performance of the algorithms was evaluated. Results: Of the 104 patients flagged by the algorithms, generalist physicians found five "diagnosed," 10 "suspected," and seven patients with "reduced suspicion." After feedback from Pompe disease specialist physicians, 19 patients remained clinically plausible for Pompe disease, resulting in a specificity of 18.27% for the AI. Estimating from the remaining plausible patients, the prevalence of Pompe disease for the greater Salzburg region [incl. Bavaria (Germany), Styria (Austria), and Upper Austria (Austria)] was one in every 18,427 people. Phenotypes for patient cohorts with an approximated onset of symptoms above or below 1 year of age were established, which correspond to infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), respectively. Conclusion: Our study shows the feasibility of Symptoma's AI-based approach for identifying rare disease patients using retrospective EHRs. Via the algorithm's screening of an entire EHR population, a physician had only to manually review 5.47 patients on average to find one suspected candidate. This efficiency is crucial as Pompe disease, while rare, is a progressively debilitating but treatable neuromuscular disease. As such, we demonstrated both the efficiency of the approach and the potential of a scalable solution to the systematic identification of rare disease patients. Thus, similar implementation of this methodology should be encouraged to improve care for all rare disease patients.

An Innovative Tool for Evidence-Based, Personalized Treatment Trials in Mucopolysaccharidosis.

Mucopolysaccharidosis (MPS) is a group of rare metabolic diseases associated with reduced life expectancy and a substantial unmet medical need. Immunomodulatory drugs could be a relevant treatment approach for MPS patients, although they are not licensed for this population. Therefore, we aim to provide evidence justifying fast access to innovative individual treatment trials (ITTs) with immunomodulators and a high-quality evaluation of drug effects by implementing a risk-benefit model for MPS. The iterative methodology of our developed decision analysis framework (DAF) consists of the following steps: (i) a comprehensive literature analysis on promising treatment targets and immunomodulators for MPS; (ii) a quantitative risk-benefit assessment (RBA) of selected molecules; and (iii) allocation phenotypic profiles and a quantitative assessment. These steps allow for the personalized use of the model and are in accordance with expert and patient representatives. The following four promising immunomodulators were identified: adalimumab, abatacept, anakinra, and cladribine. An improvement in mobility is most likely with adalimumab, while anakinra might be the treatment of choice for patients with neurocognitive involvement. Nevertheless, a RBA should always be completed on an individual basis. Our evidence-based DAF model for ITTs directly addresses the substantial unmet medical need in MPS and characterizes a first approach toward precision medicine with immunomodulatory drugs.

Individual Treatment Trials-Do Experts Know and Use This Option to Improve the Treatability of Mucopolysaccharidosis?

Mucopolysaccharidoses (MPS) are a group of rare, heterogeneous, lysosomal storage disorders. Patients show a broad spectrum of clinical features with a substantial unmet medical need. Individual treatment trials (ITTs) might be a valid, time- and cost-efficient way to facilitate personalized medicine in the sense of drug repurposing in MPS. However, this treatment option has so far hardly been used-at least hardly been reported or published. Therefore, we aimed to investigate the awareness and utilization of ITTs among MPS clinicians, as well as the potential challenges and innovative approaches to overcome key hurdles, by using an international expert survey on ITTs, namely, ESITT. Although 74% (20/27) were familiar with the concept of ITTs, only 37% (10/27) ever used it, and subsequently only 15% (2/16) published their results. The indicated hurdles of ITTs in MPS were mainly the lack of time and know-how. An evidence-based tool, which provides resources and expertise needed for high-quality ITTs, was highly appreciated by the vast majority (89%; 23/26). The ESITT highlights a serious deficiency of ITT implementation in MPS-a promising option to improve its treatability. Furthermore, we discuss the challenges and innovative approaches to overcome key barriers to ITTs in MPS.

Quality of life in patients with Fabry's disease: a cross-sectional study of 86 adults.

Background: Fabry disease (FD) is a multi-organ disorder associated with severe physical and psychological impairments, particularly in adulthood. To date, comprehensive data on the psychological burden of FD are lacking. The present study assessed quality of life (QOL) in a representative cohort of adults with FD. Methods: Patient-reported outcome measures were retrospectively analyzed in 86 adults with FD (49.6±16.6 years; 62.8% female) and compared to adults with congenital heart defects (ACHD) which is another lifelong disease and affliction. QOL was assessed using the European Quality of Life 5 Dimensions 5 Levels questionnaire (EQ-5D-5L). Results: Subjects affected by FD reported an overall reduced QOL (EQ-VAS: 71.8±20.0). Most frequently reported complaints occurred within the dimensions pain/discomfort (69.7%), daily activities (48.9%) and anxiety/depression (45.4%). Compared to ACHD, individuals with FD scored significantly lower in the areas of pain/discomfort, usual activities and mobility (all P<0.05). Older age and female sex were particularly associated with diminished QOL (P=0.05). Conclusions: Patients with FD are at high risk for impaired QOL. They require additional support to cope with disease-related challenges. Increased attention should be directed towards improving their subjective well-being to potentially increase their QOL and long-term health outcomes.

Enalapril and Enalaprilat Pharmacokinetics in Children with Heart Failure Due to Dilated Cardiomyopathy and Congestive Heart Failure after Administration of an Orodispersible Enalapril Minitablet (LENA-Studies).

Angiotensin-converting enzyme inhibitors (ACEI), such as enalapril, are a cornerstone of treatment for pediatric heart failure which is still used off-label. Using a novel age-appropriate formulation of enalapril orodispersible minitablets (ODMTs), phase II/III open-label, multicenter pharmacokinetic (PK) bridging studies were performed in pediatric patients with heart failure due to dilated cardiomyopathy (DCM) and congenital heart disease (CHD) in five participating European countries. Children were treated for 8 weeks with ODMTs according to an age-appropriate dosing schedule. The primary objective was to describe PK parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (t-max)) of enalapril and its active metabolite enalaprilat. Of 102 patients, 89 patients (n = 26, DCM; n = 63 CHD) were included in the primary PK endpoint analysis. Rate and extent of enalapril and its active metabolite enalaprilat were described and etiology and age could be identified as potential PK modifying factors. The dosing schedule appeared to be tolerated well and did not result in any significant drug-related serious adverse events. The PK analysis and the lack of severe safety events supports the applied age-appropriate dosing schedule for the enalapril ODMTs.

The Inflammation in the Cytopathology of Patients With Mucopolysaccharidoses- Immunomodulatory Drugs as an Approach to Therapy.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases (LSDs), characterized by the accumulation of glycosaminoglycans (GAGs). GAG storage-induced inflammatory processes are a driver of cytopathology in MPS and pharmacological immunomodulation can bring improvements in brain, cartilage and bone pathology in rodent models. This manuscript reviews current knowledge with regard to inflammation in MPS patients and provides hypotheses for the therapeutic use of immunomodulators in MPS. Thus, we aim to set the foundation for a rational repurposing of the discussed molecules to minimize the clinical unmet needs still remaining despite enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT).

Current knowledge, challenges and innovations in developmental pharmacology: A combined conect4children Expert Group and European Society for Developmental, Perinatal and Paediatric Pharmacology White Paper.

Developmental pharmacology describes the impact of maturation on drug disposition (pharmacokinetics, PK) and drug effects (pharmacodynamics, PD) throughout the paediatric age range. This paper, written by a multidisciplinary group of experts, summarizes current knowledge, and provides suggestions to pharmaceutical companies, regulatory agencies and academicians on how to incorporate the latest knowledge regarding developmental pharmacology and innovative techniques into neonatal and paediatric drug development. Biological aspects of drug absorption, distribution, metabolism and excretion throughout development are summarized. Although this area made enormous progress during the last two decades, remaining knowledge gaps were identified. Minimal risk and burden designs allow for optimally informative but minimally invasive PK sampling, while concomitant profiling of drug metabolites may provide additional insight in the unique PK behaviour in children. Furthermore, developmental PD needs to be considered during drug development, which is illustrated by disease- and/or target organ-specific examples. Identifying and testing PD targets and effects in special populations, and application of age- and/or population-specific assessment tools are discussed. Drug development plans also need to incorporate innovative techniques such as preclinical models to study therapeutic strategies, and shift from sequential enrolment of subgroups, to more rational designs. To stimulate appropriate research plans, illustrations of specific PK/PD-related as well as drug safety-related challenges during drug development are provided. The suggestions made in this joint paper of the Innovative Medicines Initiative conect4children Expert group on Developmental Pharmacology and the European Society for Developmental, Perinatal and Paediatric Pharmacology, should facilitate all those involved in drug development.

Impact of low-dose calcipotriol ointment on wound healing, pruritus and pain in patients with dystrophic epidermolysis bullosa: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Wound management is a critical factor when treating patients with the inherited skin fragility disease dystrophic epidermolysis bullosa (DEB). Due to genetic defects in structural proteins, skin and mucous epithelia are prone to blistering and chronic wounding upon minor trauma. Furthermore, these wounds are commonly associated with excessive pruritus and predispose to the development of life-threatening squamous cell carcinomas, underscoring the unmet need for new therapeutic options to improve wound healing in this patient cohort. Vitamin D3 is acknowledged to play an important role in wound healing by modulating different cellular processes that impact epidermal homeostasis and immune responses. In this study, we evaluate the safety and efficacy of low-dose calcipotriol, a vitamin D3 analogue, in promoting wound healing and reducing itch and pain in patients with DEB. METHODS: Eligible DEB patients, aged ≥ 6 years and with a known mutation in the COL7A1 gene, were recruited to a placebo-controlled, randomized, double blind, cross-over phase II monocentric clinical trial. Patients were required to have at least two wounds with a minimum size of 6 cm2 per wound. The primary objective was to evaluate efficacy of daily topical application of a 0.05 µg/g calcipotriol ointment in reducing wound size within a 4-week treatment regimen. Secondary objectives were to assess safety, as well as the impact of treatment on pruritus, pain, and bacterial wound colonization in these patients. RESULTS: Six patients completed the clinical trial and were included into the final analysis. Topical low-dose calcipotriol treatment led to a significant reduction in wound area at day 14 compared to placebo (88.4% vs. 65.5%, P < 0.05). Patients also reported a significant reduction of pruritus with calcipotriol ointment compared to placebo over the entire course of the treatment as shown by itch scores of 3.16 vs 4.83 (P < 0.05) and 1.83 vs 5.52 (P < 0.0001) at days 14 and 28, respectively. Treatment with low-dose calcipotriol did not affect serum calcium levels and improved the species richness of the wound microbiome, albeit with no statistical significance. CONCLUSIONS: Our results show that topical treatment with low-dose calcipotriol can accelerate wound closure and significantly reduces itch, and can be considered a safe and readily-available option to improve local wound care in DEB patients. Trial Registration EudraCT: 2016-001,967-35. Registered 28 June 2016, https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001967-35/AT.

Benefit-Risk Assessment of Off-Label Drug Use in Children: The Bravo Framework.

A drug is granted a license for use after a thorough assessment of risks and benefits based on high-quality scientific proof of its efficacy and safety. Many drugs that are relevant to children are not licensed for use in this population implying that a thorough assessment of risks and benefits in the pediatric population has not been made at all, implying a negative risk-benefit balance in children, or implying insufficient information to establish the risk-benefit balance. Use of drugs without positive assessment of risks and benefits exposes children to potential lack of efficacy, unknown toxicity, and harm. To aid guideline committees and individual prescribers, we here present a tutorial of the Benefit and Risk Assessment for Off-label use (BRAvO) decision framework. This pragmatic framework offers a structured assessment of benefits and risks of off-label drug use, including a clinical pharmacological based approach to age-appropriate dose selection. As proof of concept and to illustrate the practical use, we have applied the framework to assess benefits and risks of off-label use of ondansetron for gastroenteritis-induced nausea and vomiting. The framework could also guide decisions on off-label use in other special populations (e.g., pregnant women, elderly, obese, or critically ill patients) where off-label drug use is frequent, thereby contributing to effective and safe pharmacotherapy.

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries]. / Heiminfusionstherapie bei Morbus Pompe: Konsensusempfehlungen für den deutschsprachigen Raum.

BACKGROUND: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy. AIMS AND METHODS: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians. RESULTS AND DISCUSSION: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT ad personam to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.

[Home infusion therapy for Pompe disease: Recommendations for German-speaking countries]. / Heiminfusionstherapie bei Morbus Pompe: Konsensusempfehlungen für den deutschsprachigen Raum.

BACKGROUND: Pompe disease is a lysosomal multisystem disorder with predominant proximal myopathy. Treatment with enzyme replacement therapy (ERT) is available requiring life-long biweekly infusions of recombinant α-glucosidase. To minimize the burden of ERT patients ask for home infusion therapy. AIMS AND METHODS: Pompe disease experts from Germany, Austria, and Switzerland discussed in two consensus meetings in 2019 and 2020 requirements for home infusion therapy, adequate execution of treatment, and the legal situation for delegating physicians. RESULTS AND DISCUSSION: Home infusion therapy is principally feasible for patients with Pompe disease if certain preconditions are fulfilled, but the decision to implement has to be made on an individual basis. The treating physician delegates the execution of ERT ad personam to nursing staff but retains full legal responsibility. Home infusion therapy has to be carried out by specially trained and qualified staff. Infusion-related risks comprise mainly allergic reactions, and adequate medical treatment must be warranted. In German-speaking countries, clear rules for conducting home infusion therapy are needed to reduce psychosocial stress for patients with Pompe disease, and providing legal certainty for delegating physicians.

Challenges in clinical trials for children and young people.

There is a well-known knowledge gap regarding the efficacy and safety of medicines in children of all ages and children are often treated with medicines off-label. Children are thus deprived of treatment based on the same quality of information that guides treatment in adults. The knowledge gap regarding efficacy and safety of medicines in children has been acknowledged by authorities and is reflected in legislation both in North America and in the European Union. Recent reports on the effects of legislation indicates that paediatric clinical trials remain a challenge.Paediatric clinical trials are needed in the entire developmental age spectrum and are especially needed in certain therapy areas. Paediatric clinical trials have special features compared with trials in adults, and these need to be taken into account. These special features include scientific issues related to small samples and heterogeneity, the consent/assent procedure, the need for age-appropriate study information, specific outcomes and safety issues related to development and maturation. Competence in paediatric clinical trials is required in both designing, planning, co-ordinating and organising paediatric clinical trials, as well as research infrastructure and networks to increase power and disseminate information and expert advice. Strengthening of paediatric clinical research is essential to facilitate generating the data that will let children enjoy new medical advances in a similar manner as adults.

Prerequisites to support high-quality clinical trials in children and young people.

Children have the right to treatment based on the same quality of information that guides treatment in adults. Without the proper evaluation of medicinal products and devices in paediatric clinical trials that are designed to meet the rigorous standards of the competent authorities, children are discriminated from advances in medicine. There are regulatory, scientific and ethical incentives to address the knowledge gap regarding efficacy and safety of medicines in the paediatric population. High-quality clinical trials involving children of all ages can generate data that will ultimately close the knowledge gaps and support decision making.For clinical trials that enrol children, the needs are specialised and often resource intensive. Prerequisites for successful paediatric clinical trials are personnel with training in both paediatrics and neonatology and expertise in clinical trials in these populations. Moreover, national and international networks for efficient collaboration, dissemination of information, and sharing of resources and expertise are also needed, together with competent, efficient and high-quality local infrastructure with effective processes. Monitoring and oversight bodies with the relevant competence, including expertise in paediatrics, is also an important prerequisite for paediatric clinical trials. Compromise in any of these components will compromise the downstream results.This paper discusses the structures and competences needed in order to perform effective, high-quality paediatric clinical trials with the ultimate goal of better medicines and treatments for children. We propose a model of examining the process as a series of components that each has to be optimised, then all the components are actively optimised to function together as an ecosystem, and the resulting ecosystem functions well with the general research system and the healthcare delivery system.

Pharmacology of enalapril in children: a review.

Enalapril is an angiotensin-converting enzyme (ACE) inhibitor that is used for the treatment of (paediatric) hypertension, heart failure and chronic kidney diseases. Because its disposition, efficacy and safety differs across the paediatric continuum, data from adults cannot be automatically extrapolated to children. This review highlights paediatric enalapril pharmacokinetic data and demonstrates that these are inadequate to support with certainty an age-related effect on enalapril/enalaprilat pharmacokinetics. In addition, our review shows that evidence to support effective and safe prescribing of enalapril in children is limited, especially in young children and heart failure patients; studies in these groups are either absent or show conflicting results. We provide explanations for observed differences between age groups and indications, and describe areas for future research.

Treating neutropenia and neutrophil dysfunction in glycogen storage disease type Ib with an SGLT2 inhibitor.

Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease type Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate (1,5AG6P) caused neutropenia in a glucose-6-phosphatase 3 (G6PC3)-deficient mouse model and in 2 rare diseases (GSD-Ib and G6PC3 deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose cotransporter sodium glucose cotransporter 2 (SGLT2). Off-label use of empagliflozin in 4 GSD-Ib patients with incomplete response to granulocyte colony-stimulating factor (GCSF) treatment decreased serum 1,5AG and neutrophil 1,5AG6P levels within 1 month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in 2 patients and tapered by 57% and 81%, respectively, in the other 2. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further demonstrated improved neutrophil function: normal oxidative burst (in 3 of 3 patients tested), corrected protein glycosylation (2 of 2), and normal neutrophil chemotaxis (1 of 1), and bactericidal activity (1 of 1) under treatment. In summary, the glucose-lowering SGLT2 inhibitor empagliflozin, used for type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement in neutrophil function resulting from the reduction of the intracellular concentration of 1,5AG6P.

Simulation Training to Improve Informed Consent and Pharmacokinetic/Pharmacodynamic Sampling in Pediatric Trials.

Background: Pediatric trials to add missing data for evidence-based pharmacotherapy are still scarce. A tailored training concept appears to be a promising tool to cope with critical and complex situations before enrolling the very first patient and subsequently to ensure high-quality study conduct. The aim was to facilitate study success by optimizing the preparedness of the study staff shift. Method: An interdisciplinary faculty developed a simulation training focusing on the communication within the informed consent procedure and the conduct of the complex pharmacokinetic/pharmacodynamic (PK/PD) sampling within a simulation facility. Scenarios were video-debriefed by an audio-video system and manikins with artificial blood simulating patients were used. The training was evaluated by participants' self-assessment before and during trial recruitment. Results: The simulation training identified different optimization potentials for improved informed consent process and study conduct. It facilitated the reduction of avoidable errors, especially in the early phase of a clinical study. The knowledge gained through the intervention was used to train the study teams, improve the team composition and optimize the on-ward setting for the FP-7 funded "LENA" project (grant agreement no. 602295). Self-perceived ability to communicate core elements of the trial as well as its correct performance of sample preparation increased significantly (mean, 95% CI, p ≤ 0.0001) from 3 (2.5-3.5) to four points (4.0-4.5), and from 2 (1.5-2.5) to five points (4.0-5.0). Conclusion: An innovative training concept to optimize the informed consent process and study conduct was successfully developed and enabled high-quality conduct of the pediatric trials as of the very first patient visit.

Current and Emerging Therapies for Mucopolysaccharidoses.

Mucopolysaccharidoses (MPSs) are caused by deficiencies of specific lysosomal enzymes that affect the degradation of mucopolysaccharides or glycosaminoglycans (GAGs). Enzyme replacement therapies are available for an increasing number of MPSs since more than 15 years. Together with hematopoietic stem cell transplantation, these enzyme therapies are currently the gold standard of causal treatment in MPS. Both treatments can improve symptoms and prognosis, but they do not cure these severe conditions. The limitations of intravenous enzyme replacement and cell therapy can be summarized as the development of immune reactions against the therapeutic molecules/cells and failure to restore enduring and sufficient drug exposures in all relevant tissues. Thus innovative approaches include small molecules and encapsulated cells that do not induce immune reactions, gene therapy approaches that aim for sustained enzyme expression, and new enzymes that are able to penetrate barriers to drug distribution like the blood-brain barrier. This chapter provides an update on the state of development of these new therapies and highlights current challenges.

Relative Bioavailability of Enalapril Administered as Orodispersible Minitablets in Healthy Adults.

The angiotensin-converting enzyme inhibitor enalapril is commonly used to treat chronic heart failure in children. Because some children are unable to swallow capsules or tablets, a new, age-appropriate, orodispersible minitablet (ODMT) containing 1 mg of enalapril was developed within the EU-funded LENA (Labeling of Enalapril from Neonates up to Adolescents) consortium. In order to support the clinical evaluation of this new formulation in children, a relative bioavailability study was performed in healthy adults, comparing the bioavailability of enalapril in the ODMT with that of a reference product (RP) Renitec, a registered standard enalapril tablet formulation. In this open-label, randomized 3-way crossover study, 24 healthy subjects received a 10-mg enalapril dose administered as (1) 2 × 5-mg tablets of the RP swallowed with water, (2) 10 × 1-mg ODMT swallowed with water, and (3) 10 × 1 mg ODMT dispersed on the tongue. When the relative bioavailability of the ODMT formulation swallowed with water was compared with that of the RP, the estimated 90%CIs for the ratio of area under the concentration-time curve (AUC0-∞ ) and or peak concentration (Cmax ) of enalapril were 92.34% to 106.49% and 91.28% to 115.72%, respectively, which are within the accepted bioequivalence limits of 80% to 125%. Following dispersion of the ODMT in the mouth, a slightly higher Cmax for enalapril was observed as compared with the RP with an upper 90%CI of 127.57%, slightly exceeding the bioequivalence limit. Taken together, it was demonstrated that the method of administration of the ODMT, swallowed or dispersed, did not significantly affect the bioavailability of enalapril.