Are there mutual interactions between candesartan and amlodipine in the combination therapy of hypertension?

Methodology and Study Course

The research consisted of 2 parts, each conducted as a randomized, open-label, crossover study testing two interventions. The first part assessed the effect of amlodipine on candesartan, and the second part assessed the effect of candesartan on amlodipine.

20 participants were included—healthy men aged 20–55 years with a BMI of 18.5–27.0. Their health status was verified 28 days before the start of the study based on medical history, physical examination, vital function measurements, ECG, and laboratory tests. Participants received candesartan (32 mg), amlodipine (10 mg), or both drugs simultaneously over 10 days in each part of the study. On the 10th day, before dose administration, blood samples were taken, with additional samples collected at specified intervals after drug administration.

Pharmacokinetic assessment of candesartan in the 1st part lasted 48 hours, while the assessment of amlodipine in the 2nd part lasted 72 hours. After sample collection, the following pharmacokinetic parameters were determined: plasma concentration before dose (C_trough), maximal plasma concentration post-dose (C_max), area under the concentration-time curve over the dosing interval (AUCτ), time to reach C_max (t_max), and biological half-life (t_1/2). Pharmacodynamics were also assessed on the 10th day by measuring systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR) before and at various intervals post-dose.

Results

Plasma levels of candesartan peaked at approximately 5 hours and declined with a t_1/2 of approximately 10 hours. No statistically significant differences in t_max, t_1/2, and C_trough were observed when candesartan was administered alone versus together with amlodipine. Plasma levels of amlodipine peaked at 6 hours and declined with a t_1/2 of approximately 50 hours. No statistically significant differences in t_max, t_1/2, and C_trough were observed when amlodipine was administered alone versus together with candesartan.

In the pharmacodynamic assessment, statistically significant differences in SBP and DBP were observed between the effects of amlodipine alone and in combination with candesartan. The maximum change in SBP and DBP was -19.5/-15.7 with amlodipine alone and -26.4/-21.3 with the combination. No statistically significant differences were observed in HR.

Adverse events were mild to moderate in intensity and resolved without consequences, with no serious adverse events reported. None of the subjects had to terminate the study prematurely due to adverse events.

Discussion and Conclusion

Co-administration of candesartan and amlodipine in healthy subjects did not affect systemic exposure to either drug. The absence of pharmacokinetic interactions can be partly attributed to the different elimination pathways of the two drugs. Candesartan is excreted renally and biliary primarily unchanged, while amlodipine is metabolized by cytochrome P450 enzymes, especially CYP3A4, which candesartan does not inhibit.

Although the study was conducted in normotensive subjects, antihypertensive effects were observed in all intervention groups. Co-administration of candesartan and amlodipine reduced BP more than amlodipine alone but similarly to candesartan alone.

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Source:

Kim J.-R., Kim S., Huh W., Ko J.-W. No pharmacokinetic interactions between candesartan and amlodipine following multiple oral administrations in healthy subjects. Drug Des Devel Ther 2018; 12: 2475–2483, doi: 10.2147/DDDT.S172568.