Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

Turner, P. Kellie; Hall, Stephen D.; Chapman, Sonya C.; Rehmel, Jessica; Royalty, Jane; Guo, Yingying; Kulanthaivel, Palaniappan

doi:10.1124/dmd.119.090092

Cited by 13 publications

(11 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This indicates that abemaciclib does not impact ET exposures, and equally that ET does not affect abemaciclib pharmacokinetics. This is consistent with the known clearance routes and lack of interaction potential between abemaciclib and anastrozole, letrozole, exemestane, and tamoxifen ( 14 – 16 ). At a dose of 150 mg Q12H, the mean steady state exposures of abemaciclib achieved in combination with anastrozole, letrozole, tamoxifen, or exemestane were consistent with the exposure associated with target inhibition in xenograft models ( 5 ).…”

Section: Discussionsupporting

confidence: 86%

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study

et al. 2022

Self Cite

View full text Add to dashboard Cite

BackgroundCyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.Patients and MethodsWomen ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0–1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.ResultsSixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.ConclusionsAbemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.Clinical Trial Registrationhttps://clinicaltrials.gov/, identifier NCT02057133

show abstract

Section: Discussionsupporting

confidence: 86%

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

“…Abemaciclib and its three metabolites M1, M2, and M3 contain a halopyrimidine group, which is an electrophilic functional toxicophore commonly known to be protein-reactive by covalent binding [ 51 ]. Although CYP3A is known as the enzyme responsible for the majority of the CYP-mediated metabolism of abemaciclib and its metabolites [ 52 ], other recent studies suggested that abemaciclib does not have a clinically meaningful effect on pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 substrates in patients with cancer [ 53 ]. Oxidative metabolism of the phenol functionality present in all identified metabolites of cloperidone (M1, M2, M3, M4, M6, M7, M8) but M5 can lead to the formation of reactive catechol/quinone/quinone-imine intermediates [ 33 , 54 ].…”

Section: Resultsmentioning

confidence: 99%

Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9

et al. 2022

View full text Add to dashboard Cite

Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug–drug interactions. However, the prediction of CYP inhibition remains challenging due to its complexity. We developed an original machine learning approach for the prediction of drug-like molecules inhibiting CYP2C9. We created new predictive models by integrating CYP2C9 protein structure and dynamics knowledge, an original selection of physicochemical properties of CYP2C9 inhibitors, and machine learning modeling. We tested the machine learning models on publicly available data and demonstrated that our models successfully predicted CYP2C9 inhibitors with an accuracy, sensitivity and specificity of approximately 80%. We experimentally validated the developed approach and provided the first identification of the drugs vatalanib, piriqualone, ticagrelor and cloperidone as strong inhibitors of CYP2C9 with IC values <18 μM and sertindole, asapiprant, duvelisib and dasatinib as moderate inhibitors with IC50 values between 40 and 85 μM. Vatalanib was identified as the strongest inhibitor with an IC50 value of 0.067 μM. Metabolism assays allowed the characterization of specific metabolites of abemaciclib, cloperidone, vatalanib and tarafenacin produced by CYP2C9. The obtained results demonstrate that such a strategy could improve the prediction of drug-drug interactions in clinical practice and could be utilized to prioritize drug candidates in drug discovery pipelines.

show abstract

“…Abemaciclib has been shown to be dependent on CYP 450 3A4 for elimination and also as a potential inhibitor of several CYP 450 enzymes (based on in vitro data); therefore, DDI studies were conducted requiring the quantification of several drugs used as substrates/probes [23]. In total, eight additional bioanalytical methods were used to support the DDI studies.…”

Section: Discussionmentioning

confidence: 99%

Quantification of Abemaciclib and Metabolites: Evolution of Bioanalytical Methods Supporting a Novel Oncolytic Agent

Wickremsinhe

Lee

2021

Bioanalysis

View full text Add to dashboard Cite

Aim: Bioanalytical methods undergo many revisions and modifications throughout drug development to meet the objectives of the study and development program. Results: Validated LC–MS/MS methodology used to quantify abemaciclib and four metabolites in human plasma is described. The method, initially validated to support the first-in-human study, was successfully modified to include additional metabolites as in vitro and in vivo information about the activity and abundance of human metabolites became available. Consistent performance of the method over time was demonstrated by an incurred sample reanalysis passing rate exceeding 95%, across clinical studies. An overview of the numerous methods involved during the development of abemaciclib, including the quantification of drugs evaluated as combination regimens and used as substrates during drug–drug interaction studies, is presented. Conclusion: Robust bioanalytical methods need to be designed with the flexibility required to support the evolving study objectives associated with registration and post-registration trials.

show abstract

Abemaciclib Does Not Have a Clinically Meaningful Effect on Pharmacokinetics of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 Substrates in Patients with Cancer

Cited by 13 publications

References 26 publications

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study

Abemaciclib in Combination With Endocrine Therapy for Patients With Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: A Phase 1b Study

Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9

Quantification of Abemaciclib and Metabolites: Evolution of Bioanalytical Methods Supporting a Novel Oncolytic Agent

Contact Info

Product

Resources

About