Clinical Pharmacokinetics of Enalapril and Enalaprilat in Pediatric Patients—A Systematic Review

Purpose: Enalapril has an established safety and efficacy in adults and is used in hypertension, heart failure, and renal failure. In pediatric patients, enalapril is labeled for children with hypertension and used off label in children with heart failure. The systematic literature search aims to assess the current knowledge about enalapril and its active metabolite enalaprilat pharmacokinetics in children as a basis for dose delineation for pediatric patients with heart failure.Methods: A systematic literature review was performed in the PubMed database using relevant keywords. Dose normalization of relevant pharmacokinetic parameters of the identified studies was done for comparison between different diseases and pediatric age groups.Results: The literature search has resulted in three pediatric pharmacokinetic studies of enalapril out of which Wells et al. reported about children with hypertension and Nakamura et al., and Llyod et al. presented data for pediatric heart failure patients. The area under the curve values of enalaprilat in hypertensive pediatric patients increased with respect to the age groups and showed maturation of body functions with increasing age. Dose normalized comparison with the heart failure studies revealed that although the pediatric heart failure patients of > 20 days of age showed the area under the curve a similar to that of hypertensive patients, two pediatric patients of very early age (<20 days) were presented with 5–6-fold higher area under the curve values.Conclusion: Data related to the pharmacokinetics of enalapril and enalaprilat in hypertensive patients and few data for young heart failure children are available. Comparison of dose normalized exposition of the active metabolite enalaprilat indicated similarities between heart failure and hypertensive patients and a potentially high exposition of premature patients but substantially more pharmacokinetic studies are required to have reliable and robust enalapril as well as enalaprilat exposures especially in pediatric patients with heart failure as a basis for any dose delineation.

Pharmacokinetics of enalapril in patients with arterial hypertension depending on the glomerular filtration rate

Aim. To study the pharmacokinetics of enalapril in patients with arterial hypertension, depending on the value of the prescribed dose of enalapril and the state of renal function to improve the efficiency and safety of treatment. Materials and methods. The study was performed in a group of 328 patients (107 men and 221 women aged 43 to 88 years) who received treatment for hypertension of 1-2 degrees. As the main antihypertensive drug was prescribed enalapril in doses of 2.5 to 20 mg twice a day. Patients underwent therapeutic drug monitoring to determine the concentration of enalapril and its metabolite - enalaprilat. Results. Among the examined patients in 31% of cases there was a decrease in GFR less than 60 ml/min, and in 9 (3%) patients GFR was less than 30 ml/min. This indicates a high prevalence of chronic kidney disease among patients with hypertension. During therapeutic drug monitoring enalapril in patients with hypertension and reduced GFR (less than 60 ml/min) serum concentration of the main metabolite was 1.5-2 times higher than in patients with GFR more than 60 ml/min. Conclusion. It is advisable to carry out therapeutic drug monitoring to determine the concentrations of enalapril and enalaprilat in the serum of patients receiving the drug in high doses and having impaired renal function. In the appointment of enalapril in high doses to patients with reduced GFR, the concentration of enalaprilat significantly exceeds similar indicators in patients with normal GFR and in some cases goes beyond the therapeutic range, indicating the need to consider the correction of the treatment regimen.

P05 Establishing the integrity of the continually paediatric pharmacokinetic bioanalysis for clinical trial within an academia environment using quality assessment process

BackgroundEuropean Medicines Agency (EMA) outlines criterion for validation of bioanalytical assay applied under Good Clinical Laboratory Practice (GCLP) within clinical studies. The validation is performed once and does not inevitably ensures comparable reliability over long duration of assay’s applicability. To address this hurdle, the investigator-driven ‘Labelling of Enalapril from Neonates up to Adolescents’ project (LENA) adapted quality system comparable to industry. A comprehensive set of quality measures was applied to ensure reliability of monthly quantified paediatric samples over duration of 31 months.MethodsA 3-step quality approach analysing the calibration standards (CS), quality controls (QCs) and incurred sample reanalysis (ISR) was used to established reliability of unknown samples. Unknown concentrations were reported only if results of known CS (11 levels) and QCs were within the predefined limits. A maximum deviation of ±15% was acceptable at all five QCs level. ISR was conducted for randomly selected paediatric samples to monitor the assay’s performance over time. The acceptable%difference was ±20% for at least 67% of the ISR according to international guidelines. 1,2Results38 analytical runs were conducted for two drugs (enalapril/enalaprilat) from February 2016 to August 2018. Calibration curve evaluation accounted for exclusion of four enalapril and five enalaprilat runs. Additional investigation of QCs resulted in further exclusion of two enalapril and one enalaprilat runs. Within 32 valid runs 820, QCs were measured for enalapril and enalaprilat. 94% enalapril and 89% enalaprilat QCs were within limits (±15%). This set ensured reliable determination of 1262 LENA paediatric study samples. 93 and 104 incurred samples for enalapril and enalaprilat were reanalysed. ISR for enalapril (70%) and enalaprilat (67%) was also within guidelines.1,2ConclusionThe analysis of bioanalytical data ensured the reliability of reported unknown concentrations. It ensured consistent and reliable pharmacokinetic data from first to the last LENA study patient.ReferencesGuideline on bioanalytical method validation. European Medicines Agency, London, UK ( 2011).Guidance for Industry Bioanalytical Method Validation. US Department of Health and Human Services, US FDA, Rockville, MD, USA ( 2018).Disclosure(s)Mohsin Ali, Jutta Tins, Bjoern B Burckhardt declare that there is no conflict of interest. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)

A Liquid Chromatography-Tandem Mass Spectrometry Method for Evaluation of Two Brands of Enalapril 20 mg Tablets in Healthy Human Volunteers

Enalapril is an angiotensin-converting enzyme inhibitor used for treatment of hypertension and chronic heart disease. Enalaprilat is its active metabolite responsible for the activity. This study aimed to develop and validate a method for enalapril and enalaprilat analysis and to determine the bioequivalence of two tablet formulae of enalapril. LC-MS/MS bioanalytical method was developed and validated and then applied to evaluate the bioavailability of two enalapril formulae. Antihyperglycemic sitagliptin was used as internal standard (IS). The method was accurate for the within- and between-days analysis, and precise CV% was <5%, being linear over the calibration range 1.0–200.0 ng/ml. Stability was >85% and the LOD was 0.907 and 0.910 ng/ml for enalapril and enalaprilat, respectively, and LLOQ was 1 ng/ml. The pharmacokinetic parameters Cmax, tmax, AUC0–72, and AUC0–∞ values of enalapril and enalaprilat of the two formulae were calculated and nonsignificant differences were found. A linearity, specific, accurate, and precise method was developed and applied for the analysis of enalapril and enalaprilat in human plasma after oral administration of two formulae of enalapril 20 mg tablets in healthy volunteers. Depending on the statistical analysis it was concluded that the two enalapril formulae were bioequivalent.

EVALUATION OF THE APPLICABILITY OF A CHILD-APPROPRIATE HIGH THROUGHPUT HPLC-MS/MS METHOD FOR THE DETERMINATION OF ENALAPRIL AND ENALAPRILAT IN SMALL SAMPLE VOLUMES OF SERUM AND URINE WITHIN A GCLP-COMPLIANT ENVIRONMENT

BackgroundHeart failure is a life-threatening disease in neonates up to adolescents. The angiotensin-converting enzyme inhibitor enalapril is a recommended therapy in paediatric heart failure, although it is not labelled for patients Objective: Proof of concept of the paediatric tailored assays by verification of the reliable conduct of sample analysis according to international bioanalytical guidelines and determination of enalapril and its active metabolite enalaprilat in the LENA phase I study.MethodsAll LENA phase I samples were analysed applying the developed high throughput analysis for enalapril and enalaprilat via HPLC-MS/MS. According to the established LENA GCLP-compliant quality system, the evaluation of all study samples was conducted by using freshly prepared quality standards to obtain calibration curves of enalapril and enalaprilat in serum and urine.ResultsIn total, 22 calibration curves in serum and 7 in urine were required to investigate all samples of the phase I study of LENA. All 29 calibration curves complied with the limits of FDA and EMA bioanalytical guidelines and the applicability of the established high throughput method in the GCLP environment was proven. About 2100 study samples were successfully determined within 26 days.ConclusionThe developed paediatric tailored high throughput HPLC-MS/MS analysis proved its applicability in a GCLP-compliant environment and is suitable for the upcoming phase II and phase III studies of the LENA project focussing on paediatric patients.The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA).