Work package 7: Bioavailability and Food Effect in Healthy Adults
Work package leader
Description of the work package
This work package is led by Professor Dr. Jan de Hoon of the Center for Clinical Pharmacology (CCP) at the University Hospitals of Leuven. CCP is a medium-sized Academic Research Organisation offering a professional environment for conducting phase I and early phase II clinical trials according to ICH/GCP guidelines.
The Principal Investigator Prof. de Hoon is responsible for the conduct of the relative bioavailability study in healthy adult subjects, which will investigate the relative bioavailability between the ODMT and a standard formulation of enalapril, and the effect of oral versus gastric/intestinal absorption of the ODMT on enalapril and enalaprilat pharmacokinetic data. The bioanalytical pharmacokinetic analysis related to this work package will be conducted by the team in work package "Pharmacokinetic and Modeling & Simulation".
The study in healthy adults was completed successfully in October 2014.
These results of this study indicate that 10 x1mg ODMT (OroDispersibleMiniTablets) when swallowed with water is bioequivalent to 2 x 5 mg Renitec® tablets in healthy adults. When comparing the ODMT dissolved on the tongue to the ODMT swallowed, the estimated 90% confidence intervals for the ratio of AUC0-tz, AUC0-∞ and Cmax of enalaprilate were all in a range of 0.8 to 1.25 indicating a similar rate and extent of drug absorption. Apart from a mild to moderate bitter taste, especially when the minitablets were dispersed on the tongue, the new ODMT formulation containing 1 mg of enalapril per minitablet, was generally well tolerated.
On the basis of these results it can be concluded that a dose adjustment of enalapril due to the new ODMT formulation in the further paediatric LENA trials for neonates, infants, children and adolescents is not indicated. Moreover, it can be expected that, whether the ODMT will be swallowed with water or dispersed in the mouth will not significantly affect the bioavailability of enalapril.
The tasks included in our work package are described below:
- Protocol development: There is comprehensive information available on the pharmacokinetic behaviour of the standard marketed enalapril tablets in adults. However, for the new galenic formulation of orodispersible minitablets, pharmacokinetic data have to be provided in order to show the relative availability vs. the standard formulation. This is needed in order to adjust the doses to be used in the paediatric clinical studies. Since enalapril undergoes hepatic conversion to the active compound enalaprilat, it also needs to be investigated whether the PK of the enalapril ODMT is affected by rapid swallowing of the tablet versus dissolution in the oral cavity followed by oral absorption.
A state-of-the-art protocol and a related patient information sheet/informed consent form has been prepared and received clinical trial authorisation and a favourable opinion from the responsible ethics committee.
- Conduct of the relative bioavailability study in adult healthy subjects: This has been conducted as an open, randomised, three-way cross-over, active comparator-compared, single-dose pharmacokinetic study in 24 healthy adult subjects. All subjects have received the following treatments, each of which was separated by a wash-out period of 7 days:
• Treatment A: Renitec® – 2 tablets of 5 mg (10 mg total) to be administered with 250 ml water (fasting)
• Treatment B: Paediatric ODMT – 10 tablets of 1.0 mg (10 mg total) to be administered with 250 ml water (fasting).
• Treatment C: Paediatric ODMT – 10 tablets of 1.0 mg (10 mg total) to be administered after wetting mouth with 20 ml water with the instruction to allow the tablets to melt on the tongue. No further water or food intake permitted for 2 hours after Administration.
The total dose of 10 mg enalapril resembles a dose of 0.14 mg/kg based on a weight of 70 kg. This is slightly higher than the starting dose in children. Male or female healthy adult volunteers between 18-55 years of age with a glomerular filtration rate in the normal range and who are taking no medication were eligible for this study. Key exclusion criteria include laboratory parameters out of the normal range, existing or suspected pregnancy, cardiac or nephrologic disease, known sensitivity to ACE inhibitors, history of angioedema with ACE inhibitors, and idiopathic or hereditary angioedema. The pharmacokinetic data were analysed using state-of-the-art methodologies taking into account the existing regulatory guidelines. Enalapril and enalaprilat PK were determined and used to derive the conversion rate between enalapril and enalaprilat. The study was performed according to the LENA Quality Management System in close collaboration and under supervision of work package 4.
- Reporting of the relative availability study results and publication: The description of the study concept, performance and results will be documented in an ICH-conforming Final Study Report in close collaboration with work package 5, work package 1, work package 13 and work package 4. A publication strategy will be defined by the LENA consortium and will form the basis for the preparation and submission of the publication(s) for this relative bioavailability study. The quality-assured data obtained in this task will provide the rationale for the final dose selection in the clinical studies involving paediatric heart failure patients.