025P Queen Elizabeth II Conference Centre London
Pharmacology 2014

 

 

Comparative Bioavailability Study of a Fixed Dose Combination of Amlodipine and Enalapril

S Chung1, O Burns2, J Bullman3, A Stylianou4, S Cole5. 1Alternative Discovery & Development, GlaxoSmithKline Research & Development Ltd, Brentford, Middlesex, UK, 2Clinical Pharmacology Science & Study Operations, GlaxoSmithKline Australia Pty Ltd, Abbotsford, Victoria, Australia, 3Clinical Pharmacology, Modelling & Simulation, GlaxoSmithKline Research & Development Ltd, Stevenage, Hertfordshire, UK, 4Clinical Statistics, GlaxoSmithKline Research & Development Ltd, Stevenage, Hertfordshire, UK, 5Stiefel, a GlaxoSmithKline Company, Product Development & Analytical Sciences, RTP, North Carolina, USA

Background: A fixed dose combination (FDC) of amlodipine and enalapril is undergoing development to provide an alternative treatment option to simplify treatment regimens and potentially improve compliance in patients who are already taking these medicines individually for hypertension. This pilot study was designed to evaluate the relative bioavailability of a prototype FDC formulation compared to the individual products of amlodipine and enalapril given concurrently as separate tablets.

Methods: This was an open-label, randomised, single dose, two-way crossover study (Study ANE116798) conducted in 15 healthy male (n=9) and female (n=6) subjects aged 18–65 years. The two treatments, 1 x 5 mg amlodipine besilate tablet and 1 x 20 mg enalapril maleate tablet or 1 x amlodipine besilate/enalapril maleate 5 mg/20 mg tablet, were administered orally after an overnight fast. There was a washout period of 14 days between dosing sessions. Blood samples were collected up to 144 hours post-dose for measurement of plasma concentrations of amlodipine, enalapril, and enalaprilat (the active metabolite of enalapril) by validated high performance liquid chromatography mass spectrometry. Following loge-transformation, area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC0-inf) (defaulting to the time of last quantifiable concentration, AUC0-t, if AUC0-inf could not be consistently determined) and maximum plasma concentration (Cmax) of the analytes were separately analysed using a mixed effects model with fixed effect terms for treatment and period, and subject as a random effect. The study was funded by GlaxoSmithKline.

Results: The 90% confidence intervals for the geometric mean ratios for AUC and Cmax for amlodipine, enalapril and enalaprilat for the FDC compared with the reference coadministered tablets were within the accepted bioequivalence range of 0.80 to 1.25. Adverse events (AEs) were reported by 7 (47%) and 12 (80%) subjects following administration of the FDC and reference, respectively. The most common AE was headache. No subject had a serious AE or an AE leading to withdrawal.

Analyte Parameter Geometric LS Mean Ratio (FDC:Ref) 90% CI of ratio %CVw
n Ref n FDC
Amlodipine AUC0-t 15 119.55 15 113.23 0.95 0.88, 1.02 12.0
AUC0-inf 10 123.10 7 128.01 1.04 0.87, 1.24 20.8
Cmax 15 3.65 15 3.97 1.09 1.00, 1.19 13.2
Enalapril AUC0-t 15 190.50 15 206.67 1.08 0.98, 1.20 16.2
AUC0-inf 15 191.98 13 206.68 1.08 0.95, 1.22 17.5
Cmax 15 132.84 15 130.90 0.99 0.85, 1.14 23.3
Enalaprilat AUC0-t 15 529.31 15 581.27 1.10 1.01, 1.20 13.6
Cmax 15 63.13 15 68.96 1.09 0.96, 1.24 19.6
Units are ng/mL for Cmax and ng.h//mL for AUC0-t and AUC0-inf.LS = least squares; CVw = within-subject coefficient of variation.

Conclusion: The prototype FDC of amlodipine besilate and enalapril maleate had comparable bioavailability and tolerability to the reference coadministered tablets.