Bioequivalence evaluation of two brands of enalapril 20mg tablets (narapril and renitec) in healthy human volunteers

Abstract

The bioequivalence of two brands of enalapril 20 mg tablets was demonstrated in 24 healthy human volunteers after a single oral dose in a randomized cross-over study, conducted at IPRC, Amman, Jordan. Reference (Renitec, MSD, Netherlands) and test (Narapril, Julphar, UAE) products were administered to fasted male volunteers; blood samples were collected at specified time intervals, plasma separated and analysed for enalapril and its active metabolite (enalaprilat) using a validated LC-MS/MS method at Cartesius Analytical Unit, Institute of Biomedical Sciences, USP, Sao Paulo, Brazil. The pharmacokinetic parameters AUC(0-t), AUC(0-infinity), Cmax, Tmax, T(1/2) and elimination rate constant were determined from plasma concentration-time profile for both formulations and were compared statistically to evaluate bioequivalence between the two brands, using the statistical modules recommended by FDA. The analysis of variance (ANOVA) did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence. Based on these statistical inferences it was concluded that the two brands exhibited comparable pharmacokinetic profiles and that Julphar's Narapril is bioequivalent to Renitec of MSD, Netherlands.

Determination of enalapril and enalaprilat in small human serum quantities for pediatric trials by HPLC–tandem mass spectrometry

“…The recoveries were 75.92–88.69% for enalapril, 76.13–92.62% for enalaprilat and 74.71–88.49% for IS, all with relative standard deviations below 10% (Table ). The values were comparable with literature values (Lima et al , ; Gonzalez et al , ; Lu et al , ; Najib et al , ) and higher than those attained by liquid–liquid extraction (Gu et al , ). The matrix effects were pronounced in this setting, leading to an ion suppression of −70.14 to −76.87% for enalapril, −63.11 to −78.45% for enalaprilat and −61.39 to −69.82% for IS.…”

“…Various other technologies have emerged for the determination of enalapril and enalaprilat in biological samples like enzyme kinetic applications (Thongnopnua and Poeaknapo, 2005) and gas chromatography-tandem mass spectrometry (MS) analysis after derivatization (Shioya et al, 1992), but HPLC-tandem MS appears to be most suitable owing to its superior selectivity, which is important in patients receiving polypharmacotherapy, and the fact that it is a readily available platform. A MEDLINE search yields seven publications on enalapril and enalaprilat determination using HPLC-tandem MS (Ghosh et al, 2011;Gonzalez et al, 2010;Gu et al, 2004;Lee et al, 2003;Lima et al, 2009;Lu et al, 2009;Najib et al, 2003) with sample volumes for assay conduction ranging between 500 and 200 mL. However, blood sample volumes for pediatric studies, especially in neonates, are limited, and reduction of the blood sample quantities needed is critical for modern pediatric trial designs that implement extensive measurement of pharmacodynamic humoral biomarkers (Abdel-Rahman et al, 2007;Day et al, 2009).…”

An integrated Physiology-Based Model for the Interaction of RAA System Biomarkers With Drugs

“…38 Age, weight, and height were chosen to match the trial data from Najib et al 18 ; these parameters were used subsequently to develop the enalapril model (mean 23.25 ± 4.55 years old, 73.38 ± 9.39 kg weight, 175.96 ± 7.44 cm height). These demographic parameters were sufficiently similar to the data of the enalaprilat trial (25 ± 3 years old, 64 ± 10 kg weight, Hockings et al, "young population" 39 ), such that the final models could be combined and interpreted as a single representative individual (23.25 years old, 73.38 kg weight, 175.96 cm height).…”

“…Because the exact number of enalapril-binding sites is unknown (as these are present in both circulating and tissue bound ACE, primarily in the lung and tissue beds 44 ), the values of the species "ACE" and both binding constants were estimated from a dataset on enalapril IV administration 39 and from oral enalapril data, 18 with "ACE" being 9.00 mM, the binding constant of enalaprilat to ACE 0.1 1/minute and the respective dissociation constant 0.001 1/minute.…”

“…Between drug administrations, a 20,000 min break was inserted to allow the system to return to steady state after weaning off of the pharmacodynamic effect of the respective drug. For enalapril, HPLC-tandem MS PK measurements were available, 18 such that these were superimposed on the angiotensin data, as more indirect enalapril quantification methods have IC50 Ang2 = 50% inhibition constant of angiotensin II; Inhibitor Hill-Factor = inhibitor concentration modified by Hill-Factor (aliskiren for 4.1, enalaprilat and benazepril for 4.2, losartan for (5)); 4.1 refers to Renin-reaction, 4.2 to ACE-Reaction; IC50 Hill2Factor Inhibitor = 50% inhibition constant of enalaprilat, benazepril or aliskiren modified by Hill-Factor; Enaat = enalaprilat; PRA= plasma renin activity; k Enaatbound = binding constant enalaprilat-ACE; k Enaat=ACEdiss = dissociation constant enalaprilat from ACE; ACE= concentration of angiotensin converting enzyme; PE= percentage error; C= concentration; R= ratio; obs = observed; pred = predicted; APE= absolute percentage error. a tendency to overestimate enalapril and enalaprilat concentrations.…”