Effects of rifampicin on antineoplastic drug pyrotinib maleate pharmacokinetics in healthy subjects

Cai, Ming-min; Dou, Ting; Tang, Lu; Sun, Qiuyue; Zhai, Zi-hong; Wang, Huiping; Qian, Wei

doi:10.1007/s10637-022-01241-7

Cited by 6 publications

(5 citation statements)

References 11 publications

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“…CYP3A4 expression was not detected in present study, while a recent pharmacokinetic study demonstrated significant increase regarding pyrotinib exposure when pyrotinib was combined with CYP3A4 inhibitor itraconazole [ 39 ]. Concomitant use with CYP3A4 inducer rifampicin significantly reduced pyrotinib exposure [ 43 ]. Therefore, risky interaction between pyrotinib and potential CYP3A inhibitors or inducers should be assessed in clinics.…”

Section: Discussionmentioning

confidence: 99%

Pyrotinib-based treatments in HER2-positive breast cancer patients with brain metastases

Yan

et al. 2022

Annals of Medicine

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Objectives Extensive application of anti-HER2 targeted therapy improves significantly the HER2-positive advanced breast cancer (BC) prognosis, however, it is still difficult to treat brain metastasis. In current study, we explored effective approaches via combining pyrotinib to treat brain metastasis in patients with HER2-positive advanced BC based upon clinical data. Materials and methods Current study included 61 HER2-positive BC patients with brain metastases (BM) who were treated by pyrotinib-based regimens. The systemic regimens included pyrotinib combined with capecitabine, pyrotinib combined with nab-paclitaxel, and pyrotinib combined with vinorelbine. Patients’ progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR) and objective response rate (ORR), as well as drug-related adverse events (AEs) in regard of each combination regimen were analyzed. Results Pyrotinib-based systemic therapy resulted in 8.6 months median PFS (mPFS) and 18.0 months median OS (mOS) among the BM patients. Regarding different regimens, the combination of pyrotinib with nab-paclitaxel was superior to the combination with capecitabine and vinorelbine with respect to PFS and OS. The central nervous system (CNS) ORR did not showcase significant difference among 3 regimens, however, nab-paclitaxel combined regimen obtained the best peripheral ORR (84.6%) ( p ≤ .05). Conclusions Pyrotinib-based combination therapy is safe for HER2-positive brain metastasis treatment. Compared with vinorelbine or capecitabine, pyrotinib combined with nab-paclitaxel is more effective with less toxicity, which is the preferable regimen for HER2-positive brain metastasis. KEY MESSAGES Present investigation investigated effective methods through combining pyrotinib to treat brain metastasis with HER2-positive advanced brain cancer. The outcomes verified that pyrotinib-based combination therapy was safe and efficient to treat HER2-positive brain metastasis. Therefore, it is effective to treat brain metastasis applying anti-HER2 targeted therapies although pyrotinib showcases efficiency regarding its treatments for the metastasis.

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Section: Discussionmentioning

confidence: 99%

Pyrotinib-based treatments in HER2-positive breast cancer patients with brain metastases

Yan

et al. 2022

Annals of Medicine

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“…A previous article [10], reported that pyrotinib pharmacokinetics were signifcantly afected by itraconazole, with increased exposure levels, decreased clearance rate (CL), and prolonged t 1/2 . Meanwhile, decreased exposure levels of pyrotinib were obtained with coadministration of the strong CYP3A4 inducer rifampin [11]. Tese results suggest that the pharmacokinetic characteristics of pyrotinib are signifcantly afected by a strong CYP3A4 activity regulator.…”

Section: What Is Known and Objectivementioning

confidence: 88%

Effect of Fluconazole on the Pharmacokinetics of Pyrotinib Maleate: A Single-Center, Open, Single-Dose, Self-Controlled Study in Healthy Chinese Participants

Song

Zhang

Chen

et al. 2023

Journal of Clinical Pharmacy and Therapeutics

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What Is Known and Objective. Pyrotinib maleate, also known as pyrotinib, is an irreversible dual receptor tyrosine kinase inhibitor that primarily targets the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Cytochrome P450 3A4 (CYP3A4) enzyme mainly catalyzes pyrotinib, and its metabolism is influenced apparently by CYP3A4 strong inhibitor, but the effect of CYP3A4 moderate inhibitor is still unclear as a moderate inhibitor of CYP3A4 enzyme. This study evaluated the effect of fluconazole, a widespread antifungal medication, on the pharmacokinetics and safety tolerance of pyrotinib. Methods. This study was an open, single-dose, and self-controlled clinical trial. Eighteen healthy Chinese participants were enrolled in this study. All participants were administered fluconazole on days 6–18 and pyrotinib on days 1 and 9. The maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the concentration–time curve from time 0 to the last measurable concentration (AUC0−t), area under the concentration–time curve from time 0 extrapolated to infinity (AUC0−∞), terminal elimination half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) were calculated using WinNonlin software (version 8.1). Safety tolerance was assessed throughout the process. Results and Discussion. Compared with the single administration of pyrotinib, the exposure level was enhanced significantly after the coadministration of pyrotinib and fluconazole. The geometric mean ratios (pyrotinib + fluconazole/pyrotinib alone) of Cmax, AUC0−t, and AUC0−∞ were 2.16, 3.6, and 3.5, respectively. The parameter of t1/2 is 14.16 h and 24.03 h, and CL/F is 275.06 L/h and 78.42 L/h, for pyrotinib alone and with fluconazole. No serious adverse events were reported in this trial, and no participant withdrew from the trial because of adverse events. What Is New and Conclusion. The PK profile of pyrotinib, a CYP3A4 substrate, was significantly influenced by fluconazole, with increased exposure levels and prolonged t1/2. Dosage adjustment is suggested for the clinical application of pyrotinib when coadministered with fluconazole or other CYP3A4 inhibitors/inducers.

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“… 26 For instance, the co‐administration of pyrotinib and rifampicin in healthy individuals induced significant changes in the metabolism of rifampicin. 27 Zhang et al employed berberine as the pharmacokinetic marker to investigate the potential interaction between Gancao and Huanglian. It was found that the intestinal absorption and exposure of Huanglian were suppressed by Gancao caused by the formation of sediment, which reduced the solubility and extracted amount of berberine.…”

Section: Discussionmentioning

confidence: 99%

“…A previous clinical trial reported that over one third of patients suffered severe drug interactions and about half outpatients also showed adverse drug interactions due to inappropriate medication usage 26 . For instance, the co‐administration of pyrotinib and rifampicin in healthy individuals induced significant changes in the metabolism of rifampicin 27 . Zhang et al employed berberine as the pharmacokinetic marker to investigate the potential interaction between Gancao and Huanglian.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic study on the effect of ligustrazine–tangeretin co‐administration on the pharmacokinetics of ligustrazine and its potential mechanism in rats

Liu¹,

Liu²,

Qian³

et al. 2023

Pharmacology Res & Perspec

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Both ligustrazine and tangeretin are usually prescribed in the treatment of cardiovascular diseases, which makes their co‐administration possible. The investigation of the interaction between ligustrazine and tangeretin is necessary for the clinical compatibility of their source herbs. This study aimed to investigate the interaction of ligustrazine and tangeretin during their co‐administration. The pharmacokinetics of ligustrazine (15 mg/kg) was investigated in the presence of 50, 100, and 150 mg/kg tangeretin in rats with six of each. A single dose of ligustrazine was set as the control. The effect of tangeretin on the in vitro metabolic stability of ligustrazine was also investigated in rat liver microsomes. Tangeretin significantly reduced the system exposure of ligustrazine under all experimental concentrations. Specifically, tangeretin reduced the AUC (from 48.86 ± 12.57 to 41.02 ± 4.85 (50 mg/kg tangeretin), 31.47 ± 5.26 (100 mg/kg tangeretin), and 27.55 ± 9.60 (150 mg/kg) μg/mL × h), MRT (from 7.05 ± 0.26 to 6.33 ± 0.48, 5.53 ± 0.68, and 5.21 ± 1.31 h), Cmax (from 7.45 ± 0.44 to 6.03 ± 0.44, 5.24 ± 0.47, and 5.02 ± 0.56 μg/mL), and t1/2 (from 5.90 ± 1.27 to 4.84 ± 1.19, 3.48 ± 1.33, 3.09 ± 0.62 h) in rats. In vitro, tangeretin also reduced the metabolic stability of ligustrazine behaved as the decreased half‐life and increased intrinsic clearance rate. Co‐consumption of ligustrazine with tangeretin induced interactions, which shortens the system exposure of ligustrazine. This study provides theoretical guidance for the clinical prescription of ligustrazine‐ and tangeretin‐containing herbs.

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Effects of rifampicin on antineoplastic drug pyrotinib maleate pharmacokinetics in healthy subjects

Cited by 6 publications

References 11 publications

Pyrotinib-based treatments in HER2-positive breast cancer patients with brain metastases

Pyrotinib-based treatments in HER2-positive breast cancer patients with brain metastases

Effect of Fluconazole on the Pharmacokinetics of Pyrotinib Maleate: A Single-Center, Open, Single-Dose, Self-Controlled Study in Healthy Chinese Participants

Pharmacokinetic study on the effect of ligustrazine–tangeretin co‐administration on the pharmacokinetics of ligustrazine and its potential mechanism in rats

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