title: Bioequivalence study of two formulations of enalapril, at a single oral dose of 20 mg (tablets): A randomized, two-way, open-label, crossover study in healthy volunteers.
abstract: BACKGROUND
  Enalapril maleate is the monoethyl ester prodrug of enalapril- at, an angiotensin-converting enzyme inhibitor indicated in the management of essential and renovascular hypertension, and in the treatment of congestive heart failure and in asymptomatic patients with left ventricular dysfunction and an ejection fraction of ≥35%. Enalapril has little pharmacologic activity until hydrolyzed in vivo to enalaprilat.
  
  
  OBJECTIVE
  The aim of the present study was to compare the bioavailability and tolerability of 2 commercial brands (test and reference formulations) of enalapril tablets (20 mg), described as the rate and extent of absorption of the active moiety, to assess their bioequivalence.
  
  
  METHODS
  This single-dose, randomized, 2-way, open-label, crossover study in healthy volunteers aged 18 to 40 years was conducted at the Clinical Pharmacology Study Unit, Hospital Clínico San Carlos (Madrid, Spain). Subjects were randomized to receive (under fasting conditions) either the test or reference formulation of enalapril (20-mg tablet) at study period 1 and the opposite formulation at study period 2. Study periods were separated by a washout period of at least 7 days. During each study period, 15 plasma extractions were made to determine enalapril and enalaprilat plasma concentrations and to calculate the pharmacokinetic (PK) properties (maximal plasma drug concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve [AUC] to the last measurable concentration [AUCt], AUC from time 0 to infinity [AUC0-∞], mean residence time, and elimination half-life [tl2]) of both. Physical examination, subject interview, laboratory analyses, electrocardiogram, and blood pressure (BP) were used to assess tolerability.
  
  
  RESULTS
  Twenty-four subjects were included in the study (12 men, 12 women; mean [SD] age, 22.8 [2.2] years [range, 19-30 years]). Of these, 1 subject (4.2%) withdrew from the study for personal reasons; thus, PK and statistical analyses included results from 23 subjects. No statistically significant sequence or period effect was found. Tmax was not statistically different between the 2 formulations, and the 90% CI calculated for Tmax for the difference of the medians was within the predefined range. The 90% CIs of the logarithmically transformed concentration-derived parameters (Cmax AUCt, and AUC0-∞) also were within the predefined range; thus, the 2 formulations are considered bioequivalent. For both formulations, systolic and diastolic BPs showed significant reductions compared with baseline values (P < 0.05). Seven adverse effects were recorded, all of them transient and none of severe intensity.
  
  
  CONCLUSIONS
  In this study of 2 commercial brands (test and reference formulations) of enalapril in healthy subjects, designed and conducted under Good Clinical Practice guidelines, a similar rate and extent of absorption for both formulations were found to be bioequivalent. Both formulations produced a significant decrease in BP values and were generally well tolerated.
authors.affiliation: Unidad de Estudios de Farmacología Clínica, Servicio de Farmacología, Clínica Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Portolés
authors.affiliation: Unidad de Estudios de Farmacología Clínica, Servicio de Farmacología, Clínica Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Terleira
authors.affiliation: Medical Department, Tecnimede Sociedade Técnico-Medicinal S.A., Prior Velho, Portugal.
authors.forename: Susana
authors.initials: S
authors.lastname: Almeida
authors.affiliation: Unidad de Estudios de Farmacología Clínica, Servicio de Farmacología, Clínica Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: García-Arenillas
authors.affiliation: MCC Analítica, Barcelona, Spain.
authors.forename: Mari-Cruz
authors.initials: MC
authors.lastname: Caturla
authors.affiliation: Medical Department, Tecnimede Sociedade Técnico-Medicinal S.A., Prior Velho, Portugal.
authors.forename: August
authors.initials: A
authors.lastname: Filipe
authors.affiliation: Unidad de Estudios de Farmacología Clínica, Servicio de Farmacología, Clínica Hospital Clínico San Carlos, Madrid, Spain.
authors.forename: Emilio
authors.initials: E
authors.lastname: Vargas
keywords: bioavailability; bioequivalence; blood pressure; clinical trial; enalapril; enalaprilat; healthy volunteers; pharmacokinetics