Concomitant administration of candesartan cilexetil in patients on paclitaxel and carboplatin combination therapy increases risk of severe neutropenia

Katsube, Yurie; Hira, Daiki; Tsujimoto, Masayuki; Koide, Hiroyoshi; Minegaki, Tetsuya; Ikeda, Yoshito; Morita, Shin; Nishiguchi, Kohshi; Takato, Tsuyoshi

doi:10.5414/cp203180

2018

DOI: 10.5414/cp203180

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Concomitant administration of candesartan cilexetil in patients on paclitaxel and carboplatin combination therapy increases risk of severe neutropenia

Yurie Katsube

Daiki Hira

Masayuki Tsujimoto

et al.

Abstract: Our data suggest that a drug-drug interaction between candesartan cilexetil and TC therapy is probable. Unlike with other ARBs, the possible increased risk for development of severe neutropenia should be taken into account when prescribing candesartan cilexetil in combination with TC therapy. .

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“…Previously, we performed a comprehensive retrospective analysis of concomitant medications to identify potential risk factors for chemotherapy-induced severe neutropenia in patients administered paclitaxel plus carboplatin combination (TC) therapy. We found that concomitant use of candesartan cilexetil, unlike that of other angiotensin receptor blockers, could result in severe neutropenia (Katsube et al, 2018). Candesartan cilexetil, an angiotensin II receptor blocker, is commonly administered for the treatment of hypertension.…”

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In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-β-D-glucuronide in the Liver

et al. 2021

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Growing evidence suggests that certain glucuronides function as potent inhibitors of cytochrome P450 (CYP) 2C8. We previously reported the possibility of drug-drug interactions between candesartan cilexetil and paclitaxel. In this study, we evaluated the effects of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide on pathways associated with the elimination of paclitaxel, including those involving organic anion-transporting polypeptide (OATP) 1B1, OATP1B3, CYP2C8, and CYP3A4. UDP-glucuronosyltransferase (UGT) 1A10 and UGT2B7 were found to increase candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide formation in a candesartan concentration-dependent manner. Additionally, the uptake of candesartan N2-glucuronide and candesartan acyl-β-D-glucuronide by cells stably expressing OATPs is a saturable process with a K m of 5.11 and 12.1 μM for OATP1B1 and 28.8 and 15.7 μM for OATP1B3, respectively; both glucuronides exhibit moderate inhibition of OATP1B1/1B3. Moreover, the hydroxylation of paclitaxel was evaluated using recombinant CYP3A4 and CYP3A5. Results show that candesartan, candesartan N2-glucuronide, and candesartan acyl-β-D-glucuronide inhibit the CYP2C8-mediated metabolism of paclitaxel, with candesartan acyl-β-D-glucuronide exhibiting the strongest inhibition (the 50% inhibitory concentration (IC 50 ) is 18.9 µM for candesartan acyl-β-D-glucuronide, 150 µM for candesartan, and 166 µM for candesartan N2-glucuronide). However, time-dependent inhibition of CYP2C8 by candesartan acyl-β-D-glucuronide was not observed. Conversely, the IC 50 values of all the compounds are comparable for CYP3A4. Taken together, these data suggest that candesartan acyl-β-D-glucuronide is actively transported by OATPs into hepatocytes, and drug-drug interactions may occur with coadministration of candesartan and CYP2C8 substrates including paclitaxel as a result of the inhibition of CYP2C8 function.

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confidence: 92%

In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-β-D-glucuronide in the Liver

et al. 2021

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Severe neutropenia with chemo + candesartan cilexetil

2018

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Candesartan Has No Clinically Meaningful Effect on the Plasma Concentrations of Cytochrome P450 2C8 Substrate Repaglinide in Humans

Piha,

Cajanus,

Engström

et al. 2024

Drug Metab Dispos

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In vitro evidence show that the acyl-β-D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 µM. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl-β-D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared to placebo, with ratios of geometric means of 1.02 [P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 (P = 0.346; 90% CI 0.90-1.43), respectively.Other pharmacokinetic variables and blood glucose concentrations were neither affected.Candesartan acyl-β-D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase (P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl-β-Dglucuronide were very low compared to its CYP2C8 inhibition constant (ratio << 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent.

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Concomitant administration of candesartan cilexetil in patients on paclitaxel and carboplatin combination therapy increases risk of severe neutropenia

Cited by 3 publications

References 0 publications

In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-β-D-glucuronide in the Liver

In Vitro Evidence of Potential Interactions between CYP2C8 and Candesartan Acyl-β-D-glucuronide in the Liver

Severe neutropenia with chemo + candesartan cilexetil

Candesartan Has No Clinically Meaningful Effect on the Plasma Concentrations of Cytochrome P450 2C8 Substrate Repaglinide in Humans

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