Click to download
Evaluation of the Bioequivalence of a Fixed Dose Combination of Amlodipine and Losartan: Results from Two Phase I Clinical Trials Background: An amlodipine and losartan fixed dose combination (FDC) of a calcium channel blocker and angiotensin II receptor type-1 blocker has the potential to simplify treatment regimens and improve compliance in patients who are already taking these medicines individually for hypertension. We evaluated the relative bioavailability (BA) and bioequivalence (BE) of test amlodipine and losartan FDC formulations in two Phase I studies. Methods: A pilot open-label, randomised, single dose, 3-way crossover study (Study AML116797) evaluated the comparative BA of two FDC formulations of amlodipine/losartan 5/100 mg (FDC1: direct compression tablet with active ingredients physically mixed; FDC2: separate granulations tablet with active ingredients physically separated) compared with amlodipine and losartan given concurrently as separate tablets. The FDC1 formulation was subsequently modified to give a faster dissolution release profile for losartan and this FDC was tested in a pivotal, open-label, randomised, single dose, 3-period, reference replicated, crossover study (Study AML116799) with two sequential groups to evaluate the BE of amlodipine/losartan 5/50 mg and 5/100 mg, compared with amlodipine and losartan given concurrently as separate tablets. The 5/100 mg dose was only to be evaluated if BE was shown for the 5/50 mg dose. Both studies were conducted in healthy male and female subjects aged 18–65 years under fasting conditions. Treatment periods were separated by a washout of at least 10 days. Blood samples were collected for measurement of amlodipine and losartan by 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 studies were funded by GlaxoSmithKline. Results: In the pilot study (n=23), the 90% confidence intervals (CIs) for the geometric mean ratio (FDC/reference) for AUC and Cmax for amlodipine, and AUC for losartan, were within the accepted BE range of 0.80–1.25. Consistent with literature, high intra-subject variability was observed for losartan Cmax (CVw: 38.7%) and 90% CIs were not within 0.80–1.25 for FDC1 (ratio: 0.88; CI: 0.72-1.06) or FDC2 (ratio: 1.12, CI: 0.92-1.36). The high variability for losartan Cmax was taken into account in determining the sample size for the pivotal study and, in accordance with regulatory guidance, an expanded BE range of 0.76–1.31 was applied for this endpoint. For FDC 5/50 mg vs. reference (n=102), the 90% CIs for the geometric mean ratio for AUC and Cmax for amlodipine, and AUC for losartan, were within the accepted BE range of 0.80–1.25. However, the losartan Cmax was outside the expanded BE range of 0.76–1.31 (ratio: 1.24, CI: 1.15–1.33, CVw: 37.0%). As BE was not shown for FDC 5/50 mg the study was terminated and FDC 5/100 mg was not evaluated. In both studies, the proportion of subjects with adverse events (AEs) was similar in FDC and reference dosing sessions (ranging from 37% to 55%). The most frequent AE in both studies was headache. One subject was withdrawn from the pilot study due to an AE of peripheral oedema (not considered by the investigator to be related to study drug). One subject had serious AEs of lower abdominal pain, flank pain, nausea and pyrexia in the pivotal study (not considered by the investigator to be related to study drug). Conclusion: The amlodipine/losartan FDC tested in the pivotal study was not bioequivalent to amlodipine and losartan administered separately in terms of losartan Cmax.
|
