Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum

Ishikawa, Emi; Yokoyama, Yuta; Chishima, Haruna; Kuniyoshi, Ouki; Sato, Itaru; Nakaya, Naoki; Nakajima, Hideo; Kimura, Motonori; Hakamata, Jun; Suehiro, Naoya; Nakada, Hideo; Ikemura, Shinnosuke; Jibiki, Aya; Kawazoe, Hitoshi; Muramatsu, Hiroshi; Suzuki, Sayo; Nakamura, Tomonori

doi:10.1016/j.jchromb.2022.123245

Cited by 8 publications

(7 citation statements)

References 27 publications

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“…Consistent with previous publications [ 28 , 31 ], the minimum drug concentrations (C min ) of osimertinib at a steady state were highly variable (6.19–380 ng/mL), and the mean C min was 139.98 ng/mL at the steady state. Compared to the methods previously reported, our newly developed method was more simple and convenient.…”

Section: Resultssupporting

confidence: 89%

“…The validated method was successfully used in our laboratory to measure the pla drug concentration at steady states of osimertinib (n = 10) and aumolertinib (n = 2) in tients with NSCLC (Table 4 and Figure 4). Consistent with previous publications [28,31], the minimum drug concentrat (Cmin) of osimertinib at a steady state were highly variable (6.19-380 ng/mL), and the m Cmin was 139.98 ng/mL at the steady state. Compared to the methods previously repor our newly developed method was more simple and convenient.…”

Section: Clinical Applicationsupporting

confidence: 87%

“…The mean Cm aumolertinib was 155.5 ng/mL, which is consistent with the published clinical trial da Brown et al [32] did not identify a relationship between osimertinib exposure efficacy, but a correlation between exposure and safety endpoints was observed. Du the small number of clinical plasma samples, the relationships between the plasma c centrations of the three drugs and their efficacy and side effects were not establishe Consistent with previous publications [28,31], the minimum drug concentrations (C min ) of osimertinib at a steady state were highly variable (6.19-380 ng/mL), and the mean C min was 139.98 ng/mL at the steady state. Compared to the methods previously reported, our newly developed method was more simple and convenient.…”

Section: Clinical Applicationmentioning

confidence: 54%

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Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Li¹,

Ma³

et al. 2022

Molecules

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The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, and furmonertinib represent a new treatment option for patients with EGFR p.Thr790 Met (T790 M)-mutated non-small cell lung cancer (NSCLC). Currently, there are no studies reporting the simultaneous quantification of these three drugs. A simple ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of osimertinib, aumolertinib, and furmonertinib concentrations in human plasma, and it was applied for therapeutic drug monitoring (TDM). Plasma samples were processed using the protein precipitation method (acetonitrile). A positive ion monitoring mode was used for detecting analytes. D3-Sorafenib was utilized as the internal standard (IS), and the mobile phases were acetonitrile (containing 0.1% formic acid) and water with gradient elution on an XSelect HSS XP column (2.1 mm × 100.0 mm, 2.5 µm, Waters, Milford, MA, USA) at a flow rate of 0.5 mL·min−1. The method’s selectivity, precision (coefficient of variation of intra-day and inter-day ≤ 6.1%), accuracy (95.8–105.2%), matrix effect (92.3–106.0%), extraction recovery, and stability results were acceptable according to the guidelines. The linear ranges were 5–500 ng·mL−1, 2–500 ng·mL−1, and 0.5–200 ng·mL−1 for osimertinib, aumolertinib, and furmonertinib, respectively. The results show that the method was sensitive, reliable, and simple and that it could be successfully applied to simultaneously determine the osimertinib, aumolertinib, and furmonertinib blood concentrations in patients. These findings support using the method for TDM, potentially reducing the incidence of dosing blindness and adverse effects due to empirical dosing and inter-patient differences.

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Section: Resultssupporting

confidence: 89%

Section: Clinical Applicationsupporting

confidence: 87%

Section: Clinical Applicationmentioning

confidence: 54%

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Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Li¹,

Ma³

et al. 2022

Molecules

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“…Osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), is a first-administration is required [8]; a validated bioanalytical method is available [9]; high interindividual variability of exposure with coefficients of variation of 27.6-37.6% is observed [10]; and a correlation between the exposure to osimertinib parent compound and the occurrence of AEs exists [11]. Osimertinib has two active metabolites, AZ5104 and AZ7550, which may be essential compounds for TDM.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study

et al. 2023

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Background: Potential novel strategies for adverse event (AE) management of osimertinib therapy, including therapeutic drug monitoring and the use of biomarkers, have not yet been fully investigated. This study aimed to evaluate (1) the relationship between exposure to osimertinib, especially its active metabolites (AZ5104 and AZ7550), and AEs, and (2) the relationship between germline polymorphisms and AEs. Methods: We conducted a prospective, longitudinal observational study of 53 patients with advanced non-small cell lung cancer receiving osimertinib therapy from February 2019 to April 2022. A population pharmacokinetic model was developed to estimate the area under the serum concentration–time curve from 0 to 24 h (AUC0–24) of osimertinib and its metabolites. Germline polymorphisms were analyzed using TaqMan® SNP genotyping and CycleavePCR® assays. Results: There was a significant association between the AUC0–24 of AZ7550 and grade ≥ 2 paronychia (p = 0.043) or anorexia (p = 0.011) and between that of osimertinib or AZ5104 and grade ≥ 2 diarrhea (p = 0.026 and p = 0.049, respectively). Furthermore, the AUC0–24 of AZ5104 was significantly associated with any grade ≥ 2 AEs (p = 0.046). EGFR rs2293348 and rs4947492 were associated with severe AEs (p = 0.019 and p = 0.050, respectively), and ABCG2 rs2231137 and ABCB1 rs1128503 were associated with grade ≥ 2 AEs (p = 0.008 and p = 0.038, respectively). Conclusion: Higher exposures to osimertinib, AZ5104, and AZ7550 and polymorphisms in EGFR, ABCG2, and ABCB1 were related to higher severity of AEs; therefore, monitoring these may be beneficial for osimertinib AE management.

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“…Therefore, improving favorable PK profiles of osimertinib may be feasible to decrease the toxicity and achieve an excellent clinical outcome. 32 Dosimertinib deuteraterated analog of osimertinib, has better pk properties that increase the concentration of the drug in plasma, achieving better clinical benefits for the safety and excretion of the drugs. Several studies showed that dosimertinib has robust in vivo antitumor efficacy and better PK profiles, with lesser toxicity than osimertinib.…”

Section: Dosimertinib: a Deuterated Osimertinibmentioning

confidence: 99%

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer

Belete¹

2022

DDDT

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Cancer is one of the deadliest diseases in the world. In 2020, 19.3 million cancer cases and 10 million deaths were reported in the world. It is supposed that the prevalence of cancer cases will rise to 28.4 million by 2040. Chemotherapy-based regimens have a narrow therapeutic index, severe adverse drug reactions, and lack metabolic stability. Besides, the metabolism of anticancer produces several non-active and toxic metabolites that reduce exposure of the target site to the parent drug. Therefore, developing better-tolerated and effective new anticancer drugs and modification of the existing anticancer drugs to minimize toxicity and increase efficacy has become a very urgent need. Deuterium incorporation reduces the metabolism of certain drugs that are breakdown by pathways involving hydrogen-carbon bond scission. For example, CYP450 mediated oxidative metabolism of drugs that involves the breakdown of a hydrogen-carbon bond affected by deuteration. Deuterium incorporation into the drug increases the half-life and reduces the dose, which provides better safety and efficacy. Deutetrabenazine is the first deuterated form of tetrabenazine approved to treat chorea associated with Huntington’s disease and tardive dyskinesia. The study revealed that Deutetrabenazine has fewer neuropsychiatric side effects with favorable safety than tetrabenazine. The current review highlights the deuterium kinetic isotope effect on drug metabolism, deuterated compound pharmacokinetic property, and safety profile. Besides, this review explains the deuterated anticancer drug development update status.

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Development and validation of a new liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of afatinib, dacomitinib, osimertinib, and the active metabolites of osimertinib in human serum

Cited by 8 publications

References 27 publications

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Determination of Osimertinib, Aumolertinib, and Furmonertinib in Human Plasma for Therapeutic Drug Monitoring by UPLC-MS/MS

Population Pharmacokinetics, Pharmacogenomics, and Adverse Events of Osimertinib and its Two Active Metabolites, AZ5104 and AZ7550, in Japanese Patients with Advanced Non-small Cell Lung Cancer: a Prospective Observational Study

Recent Updates on the Development of Deuterium-Containing Drugs for the Treatment of Cancer

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