Comparisons of the pharmacokinetics and tolerability of fixed-dose combinations of amlodipine besylate/losartan and amlodipine camsylate/losartan in healthy subjects: a randomized, open-label, single-dose, two-period, two-sequence crossover study

Abstract

BackgroundA fixed-dose combination (FDC) of amlodipine and losartan has been used to reduce blood pressure in patients whose hypertension is not sufficiently controlled with either drug alone. The aim of this study was to evaluate the pharmacokinetic (PK) characteristics and tolerability of an FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium compared to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium in healthy subjects.Subjects and methodsA randomized, open-label, single-dose, two-period, two-sequence crossover study was conducted on 46 healthy male subjects. Blood concentrations were measured by liquid chromatography–tandem mass spectrometry. Blood samples were collected up to 144 hours post dose for each period. PK parameters were calculated in each treatment group using a noncompartmental method. The 90% confidence intervals (CIs) of the geometric mean ratios of the two treatments for the maximum plasma concentration (Cmax) and the area under the concentration curve from time zero to the last quantifiable time point (AUC0–t) were estimated. Tolerability assessments were performed for all subjects who received the drug at least once.ResultsThe PK profiles of the two treatments were similar. For amlodipine, the geometric mean ratios (90% CIs) of amlodipine besylate to amlodipine camsylate for the Cmax and AUC0–t were 0.98 (0.94−1.01) and 0.97 (0.93−1.01), respectively. The corresponding values for losartan were 0.91 (0.81−1.02) and 1.05 (0.98−1.12), respectively. The incidence of adverse events was not significantly different between the two treatments, and both were well tolerated.ConclusionAn FDC of 6.94 mg amlodipine besylate (5 mg as amlodipine)/50 mg losartan potassium produced similar results to an FDC of 5 mg amlodipine camsylate/50 mg losartan potassium treatment with respect to the PK parameters of amlodipine and losartan based on Cmax and AUC0–t values. The amlodipine besylate/losartan potassium combination was well tolerated by healthy male subjects.

Population pharmacokinetic modelling to quantify the magnitude of drug-drug interactions between amlodipine and antiretroviral drugs

“…Plasma samples underwent protein precipitation with methanol, followed by evaporation of the supernatant at room temperature under nitrogen. The lower limit of quantification was 0.3 ng/mL, well below trough concentrations commonly observed in clinical practice [9,13,14].…”

<p>Comparison of Pharmacokinetics of a Fixed-Dose Combination of Amlodipine/Losartan/Rosuvastatin with Concomitant Administration of Amlodipine/Losartan and Rosuvastatin in Healthy Volunteers</p>

“…The changing pattern of blood pressure in this study was similar to that in a previous comparative pharmacokinetic study of an FDC of amlodipine and losartan. 14 Amlodipine 5 mg, losartan 100 mg, and rosuvastatin 20 mg along with a combination dosage regimen exhibited clinically significant effectiveness in patients with both dyslipidemia and hypertension. 13 In addition to the FDCs studied in this investigation, additional different combinations of these three drugs might be required to adjust and titrate dosages for individual therapy.…”

“…13 The pharmacokinetic profiles of the FDC and LC treatments of amlodipine and losartan were compared and found to be similar. 14 Consequently, to develop a triple FDC for clinical application, the equivalence of PK parameters must be confirmed between the FDC of the three drugs and the case of concomitant LC administration.…”

Pharmacokinetics, Bioequivalence, and Safety Studies of Amlodipine Besylate in Healthy Subjects

“…PK and bioequivalence evaluation of amlodipine besylate studied previously were fixed-dose combinations in healthy subjects, in which amlodipine besylate was combined with losartan or orotate. 1,7 A PK study of amlodipine besylate was to evaluate amlodipine besylate in the peripartum period including quantities of placental passage, breast milk excretion, and infant exposure when the pregnant hypertensive women used the drug during pregnancy and the postpartum period. 8 However, PK and bioequivalence studies of amlodipine besylate in healthy adult subjects under fasting and postprandial conditions have not yet been reported.…”