Pharmacokinetic and haemodynamic interactions between amlodipine and losartan in human beings

Jin Woo Park, Kyoung Ah Kim, Yong Il Kim, Ji Young Park

Research output: Contribution to journalArticle

Abstract

The combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) for the treatment of hypertension showed improved efficacy and safety. Amlodipine is mainly metabolized by cytochrome P450 (CYP) 3A4, whereas losartan is metabolized by CYP2C9 and CYP3A4. The potential pharmacokinetic interactions between amlodipine and losartan were assessed. An open-label, three-period, fixed-sequence trial was conducted. Amlodipine, losartan and combined amlodipine and losartan were administered to 24 healthy male participants during periods 1, 2 and 3, respectively, for 9 days each. The pharmacokinetics of amlodipine, losartan and EXP-3174, an active metabolite of losartan, were assessed at steady-state. Twenty participants completed the study without serious adverse events. Losartan did not influence the exposure of amlodipine at steady-state (AUCτ, 165.15 ng h/mL [amlodipine alone] vs 172.36 ng h/mL [combination], P = 0.389) [geometric mean ratio (GMR) (90% confidence interval [CI]), 1.060 (0.954-1.178)]. In addition, the exposure of EXP-3174 was not affected by amlodipine (AUCτ, 1159.46 ng h/mL vs 1105.10 ng h/mL, P = 0.295) (GMR [90% CI], 0.957 [0.891-1.027]). However, amlodipine significantly decreased the exposure of losartan at steady-state (AUCτ, 1241.50 ng h/mL vs 1082.02 ng h/mL, P = 0.006) (GMR [90% CI], 0.875 [0.813-0.942]) and increased oral clearance of losartan (84.65 L/h vs 97.26 L/h, P = 0.002). Combination use of two drugs caused additive haemodynamic changes compared to treatment of amlodipine or losartan alone. The co-administration of amlodipine and losartan was tolerable and did not cause substantial pharmacokinetic interaction, even though losartan disposition was affected. Combination use of the two drugs caused additive haemodynamic changes compared to monotherapy of amlodipine or losartan.

Original languageEnglish
Pages (from-to)345-352
Number of pages8
JournalBasic and Clinical Pharmacology and Toxicology
Volume125
Issue number4
DOIs
Publication statusPublished - 2019 Oct 1

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Amlodipine
Pharmacokinetics
Losartan
Hemodynamics
Area Under Curve
Cytochrome P-450 CYP3A
Confidence Intervals
Angiotensin Receptor Antagonists
Calcium Channels
Metabolites
Pharmaceutical Preparations
Labels
Healthy Volunteers

Keywords

  • amlodipine
  • interactions
  • losartan
  • pharmacodynamics
  • pharmacokinetics

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Cite this

Pharmacokinetic and haemodynamic interactions between amlodipine and losartan in human beings. / Park, Jin Woo; Kim, Kyoung Ah; Il Kim, Yong; Park, Ji Young.

In: Basic and Clinical Pharmacology and Toxicology, Vol. 125, No. 4, 01.10.2019, p. 345-352.

Research output: Contribution to journalArticle

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abstract = "The combination of calcium channel blockers (CCB) and angiotensin receptor blockers (ARB) for the treatment of hypertension showed improved efficacy and safety. Amlodipine is mainly metabolized by cytochrome P450 (CYP) 3A4, whereas losartan is metabolized by CYP2C9 and CYP3A4. The potential pharmacokinetic interactions between amlodipine and losartan were assessed. An open-label, three-period, fixed-sequence trial was conducted. Amlodipine, losartan and combined amlodipine and losartan were administered to 24 healthy male participants during periods 1, 2 and 3, respectively, for 9 days each. The pharmacokinetics of amlodipine, losartan and EXP-3174, an active metabolite of losartan, were assessed at steady-state. Twenty participants completed the study without serious adverse events. Losartan did not influence the exposure of amlodipine at steady-state (AUCτ, 165.15 ng h/mL [amlodipine alone] vs 172.36 ng h/mL [combination], P = 0.389) [geometric mean ratio (GMR) (90{\%} confidence interval [CI]), 1.060 (0.954-1.178)]. In addition, the exposure of EXP-3174 was not affected by amlodipine (AUCτ, 1159.46 ng h/mL vs 1105.10 ng h/mL, P = 0.295) (GMR [90{\%} CI], 0.957 [0.891-1.027]). However, amlodipine significantly decreased the exposure of losartan at steady-state (AUCτ, 1241.50 ng h/mL vs 1082.02 ng h/mL, P = 0.006) (GMR [90{\%} CI], 0.875 [0.813-0.942]) and increased oral clearance of losartan (84.65 L/h vs 97.26 L/h, P = 0.002). Combination use of two drugs caused additive haemodynamic changes compared to treatment of amlodipine or losartan alone. The co-administration of amlodipine and losartan was tolerable and did not cause substantial pharmacokinetic interaction, even though losartan disposition was affected. Combination use of the two drugs caused additive haemodynamic changes compared to monotherapy of amlodipine or losartan.",
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