Dose Individualization of Oral Multi-Kinase Inhibitors for the Implementation of Therapeutic Drug Monitoring

Noda, Shinichi; Morita, Shinya; Takato, Tsuyoshi

doi:10.1248/bpb.b21-01098

Cited by 7 publications

(3 citation statements)

References 101 publications

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“…Before developing guidelines, it is crucial to make a selection of drugs based on specific characteristics such as marked PK variability, concentration related therapeutic and adverse effects, narrow and defined target concentration range, potential serious adverse events, and a suitable and accessible laboratory assay. 1 , 6 , 8 …”

Section: Discussionmentioning

confidence: 99%

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Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review

Li,

Song,

et al. 2024

Ther Adv Med Oncol

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Background: Compared with anti-infective drugs, immunosuppressants and other fields, the application of therapeutic drug monitoring (TDM) in oncology is somewhat limited. Objective: We aimed to provide a comprehensive understanding of TDM guidelines for antineoplastic drugs and to promote the development of individualized drug therapy in oncology. Design: This study type is a systematic review. Data sources and methods: This study was performed and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement. Databases including PubMed, Embase, the official websites of TDM-related associations and Chinese databases were comprehensively searched up to March 2023. Two investigators independently screened the literature and extracted data. The methodological and reporting quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) and the Reporting Items for Practice Guidelines in Healthcare (RIGHT), respectively. Recommendations and quality evaluation results were presented by visual plots. This study was registered in PROSPERO (No. CRD42022325661). Results: A total of eight studies were included, with publication years ranging from 2014 to 2022. From the perspective of guideline development, two guidelines were developed using evidence-based methods. Among the included guidelines, four guidelines were for cytotoxic antineoplastic drugs, three for small molecule kinase inhibitors, and one for antineoplastic biosimilars. Currently available guidelines and clinical practice provided recommendations of individualized medication in oncology based on TDM, as well as influencing factors. With regard to methodological quality based on AGREE II, the average overall quality score was 55.21%. As for the reporting quality by RIGHT evaluation, the average reporting rate was 53.57%. Conclusion: From the perspective of current guidelines, TDM in oncology is now being expanded from cytotoxic antineoplastic drugs to newer targeted treatments. Whereas, the types of antineoplastic drugs involved are still small, and there is still room for quality improvement. Furthermore, the reflected gaps warrant future studies into the exposure–response relationships and population pharmacokinetics models.

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Section: Discussionmentioning

confidence: 99%

“…In multiple clinical scenarios, TDM-based dose individualization strategies have been shown to significantly improve health outcomes, including improved effectiveness, shorter hospitalization, and reduced side effects. 2 – 6 …”

Section: Introductionmentioning

confidence: 99%

Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review

Li,

Song,

et al. 2024

Ther Adv Med Oncol

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“…However, targeted oral therapy, including CDK4/6 inhibitors and tyrosine kinase inhibitors (TKIs), uses a fixed dose regardless of weight or BSA. It has been shown that there is an exposure-efficacy/toxicity outcome relationship between palbociclib [21,22] and TKIs [23,24]. Leenhardt et al showed that the plasma C trough of palbociclib has a correlation with developing high-grade NP.…”

Section: Discussionmentioning

confidence: 99%

Risk Factors for Palbociclib-Induced Early Developing Neutropenia in Patients with Hormone Receptor-Positive Metastatic Breast Cancer

Lee

Seo

et al. 2023

Cancers

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Purpose: This study aimed to determine the risk factors for palbociclib-induced grade 4 or grade 3 neutropenia (NP) requiring dose reduction or delayed treatment in patients with HR+/HER2−metastatic breast cancer in the first 3 cycles (early grade 3/4 NP) and whether the early developing grade 3/4 NP affects progression-free survival. Methods: A retrospective study using electronic medical records was conducted on patients who received palbociclib for metastatic breast cancer between January 2018 and August 2022. The early grade 3/4 NP risk factors were evaluated with univariate and multivariable logistic regression analyses. In addition, the Kaplan-Meier method was used to estimate the median progression-free survival (PFS) to analyze the effect of early grade 3/4 NP on treatment. Results: Out of the 264 patients included in this study, 173 (65.6%) experienced early grade 3/4 NP. A total of four models were applied for multivariable analysis to identify early grade 3/4 NP-developing factors. Low baseline ANC, WBC, PLT, and BSA were significant risk factors for early grade 3/4 NP; baseline ANC < 3700/mm3, WBC < 6.30 × 109/mm3, PLT < 230 × 109/mm3, and BSA < 1.58 m2 increased the risk by approximately 4.0-fold, 3.7–4.0-fold, 2.1-fold, and 2.0-fold, respectively. Early grade 3/4 NP did not affect PFS (p = 0.710), although patients with early grade 3/4 NP had more frequent dose reductions or treatment delays. Conclusions: Based on the results, low baseline ANC, WBC, PLT, and BSA were associated with early grade 3/4 NP. Patients with risk factors require careful monitoring, and this study is expected to help predict NP, which may appear in early treatment.

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Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice

Kumondai,

Ogawa,

Hayashi

et al. 2024

Pharmacology Res & Perspec

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Lenvatinib (LEN), a multitarget tyrosine kinase inhibitor used in various cancer treatments, is mainly metabolized by cytochrome P450 3A (CYP3A) enzymes. The importance of therapeutic drug monitoring (TDM) in patients administered LEN has been proposed. Although some biomarkers of endogenous CYP3A activity have been reported, their utility in dosage adjustments has not been well evaluated. This study investigated the correlation between plasma LEN concentrations and endogenous urinary CYP3A biomarkers in clinical practice. Concentrations of plasma LEN (N = 225) and CYP3A biomarkers (cortisol, 6β‐hydroxycortisol, deoxycholic acid, and 1β‐hydroxydeoxycholic acid) in urine (N = 214) from 20 patients (hepatocellular carcinoma, N = 6; thyroid cancer, N = 3; endometrial cancer, N = 8; and renal cell carcinoma, N = 3) collected for consultation for up to 1 year were evaluated using liquid chromatography–tandem mass spectrometry. Moreover, plasma trough LEN concentrations were predicted using a three‐compartment model with linear elimination for outpatients administered LEN before sample collection. Moderate correlations were observed between the quantified actual concentrations and the predicted trough concentrations of LEN, whereas there was no correlation with endogenous urinary CYP3A biomarkers. The utility of endogenous urinary CYP3A biomarkers could not be determined. However, TDM for outpatients administered orally available medicines may be predicted using a nonlinear mixed effect model (NONMEM). This study investigated the utility of endogenous urinary CYP3A biomarkers for personalized medicine and NONMEM for predicting plasma trough drug concentrations. These findings will provide important information for further clinical investigation and detailed TDM.

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Dose Individualization of Oral Multi-Kinase Inhibitors for the Implementation of Therapeutic Drug Monitoring

Cited by 7 publications

References 101 publications

Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review

Therapeutic drug monitoring guidelines in oncology: what do we know and how to move forward? Insights from a systematic review

Risk Factors for Palbociclib-Induced Early Developing Neutropenia in Patients with Hormone Receptor-Positive Metastatic Breast Cancer

Relevance of plasma lenvatinib concentrations and endogenous urinary cytochrome P450 3A activity biomarkers in clinical practice

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