Orodispersible minitablets of enalapril for use in children with heart failure (LENA): Rationale and protocol for a multicentre pharmacokinetic bridging study and follow-up safety study

Abstract

Introduction Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. Methods and Analysis Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. Ethics and dissemination Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. Trial registration numbers EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21.

Mini-Tablets: A Valid Strategy to Combine Efficacy and Safety in Pediatrics

“…The efforts of the European Union in supporting the transformation from off-label to fully licensed use of medicines for pediatrics led to the creation of the "Labeling of Enalapril from Neonates to Adolescents" (LENA) project, which included seven European countries. It aimed at clinically investigating and developing an enalapril medicinal product, easily and safely administrable to all pediatric subpopulations [14]. Concurrently, the collected data served to generate sufficient information for obtaining the approval of a PUMA for the product.…”

Tableting of mini-tablets in comparison with conventionally sized tablets: A comparison of tableting properties and tablet dimensions

“…Frequently used excipients like microcrystalline cellulose (MCC), which is known for mainly plastic deformation ( David and Augsburger, 1977 ) and agglomerated α-lactose (Tablettose® 80), which is described as a more brittle material ( Lerk, 1993 ) are investigated. Isomalt and Ludiflash® gained a certain relevance in formulation development especially for mini-tablets for paediatric use after recent publication of feasibility and clinical studies ( Bajcetic et al, 2019 ; Lura et al, 2019 ). Functionalized isomalt (galenIQ™721) mainly undergoes plastic deformation whereas d -mannitol (co-processed in Ludiflash®) has more brittle properties ( BASF, 2012 ; Bolhuis et al, 2009 ; Wu and Sun, 2007 ).…”

The Evaluation of Dynamic Compaction Analysis as a QBD Tool for Paediatric Orodispersible Minitablet Formulation

“…Orodispersible minitablets were first reported by Stoltenberg and Breitkreutz (2011) as 2 -3 mm diameter tablets that disintegrate in the oral cavity in a few seconds [24]. The risks associated to their administration like choking or aspiration are low and their acceptability and swallowability were confirmed in paediatric patients below 6 years of age [1]. However, a series of technological issues with impact on the balance between stability, mechanical properties and disintegration should be considered at the development of orodispersible minitablets, as well as the processability of the selected excipients and the compression performance.…”