- Development and validation of a bioanalytical method for the quantification of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib in human and mouse matrices using liquid chromatography-tandem mass spectrometry. [Journal Article]
- ABAnal Bioanal Chem 2019 Jun 17
- A novel method was developed and validated for the quantification of the three approved CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) in both human and mouse plasma and mouse tissue ho…
A novel method was developed and validated for the quantification of the three approved CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) in both human and mouse plasma and mouse tissue homogenates (liver, kidney, spleen, brain, and small intestine) using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). For all matrices, pretreatment was performed using 50 μL of sample by protein precipitation with acetonitrile, followed by dilution of the supernatant. Chromatographic separation of the analytes was done on a C18 column using gradient elution. A full validation was performed for human plasma, while a partial validation was executed for mouse plasma and mouse tissue homogenates. The method was linear in the calibration range from 2 to 200 ng/mL, with a correlation coefficient (r) ≥0.996 for each analyte. For both human and mouse plasma, the accuracy and precision were within ±15% and ≤15%, respectively, for all concentrations, except for the lower limit of quantification, where they were within ±20% and ≤20%, respectively. A fit-for-purpose strategy was followed for tissue homogenates, and the accuracy and precision were within ±20% and ≤20%, respectively, for all concentrations. Stability of all analytes in all matrices at different processing and storage conditions was tested; ribociclib and palbociclib were unstable in most tissue homogenates and conditions were modified to increase the stability. The method was successfully applied for the analysis of mouse samples from preclinical studies. A new ribociclib metabolite was detected in mouse plasma samples with the same m/z transition as the parent drug.
- Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. [Review]
- TATher Adv Med Oncol 2019; 11:1758835919833867
- Drug-drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to lon…
Drug-drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the 'First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications'. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.
- Multiomics Profiling Establishes the Polypharmacology of FDA-Approved CDK4/6 Inhibitors and the Potential for Differential Clinical Activity. [Journal Article]
- CCCell Chem Biol 2019 Jun 06
- The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the …
The target profiles of many drugs are established early in their development and are not systematically revisited at the time of FDA approval. Thus, it is often unclear whether therapeutics with the same nominal targets but different chemical structures are functionally equivalent. In this paper we use five different phenotypic and biochemical assays to compare approved inhibitors of cyclin-dependent kinases 4/6-collectively regarded as breakthroughs in the treatment of hormone receptor-positive breast cancer. We find that transcriptional, proteomic, and phenotypic changes induced by palbociclib, ribociclib, and abemaciclib differ significantly; abemaciclib in particular has advantageous activities partially overlapping those of alvocidib, an older polyselective CDK inhibitor. In cells and mice, abemaciclib inhibits kinases other than CDK4/6 including CDK2/cyclin A/E-implicated in resistance to CDK4/6 inhibition-and CDK1/cyclin B. The multifaceted experimental and computational approaches described here therefore uncover underappreciated differences in CDK4/6 inhibitor activities with potential importance in treating human patients.
- Targeted therapy for breast cancer in older patients. [Review]
- JGJ Geriatr Oncol 2019 Jun 03
- Older patients are one of the most relevant sub-groups of patients with breast cancer and will only gain in importance as demographic transition unfolds. Their management, in both the early and advan…
Older patients are one of the most relevant sub-groups of patients with breast cancer and will only gain in importance as demographic transition unfolds. Their management, in both the early and advanced settings, should take into consideration specific clinical needs and is made more difficult by the limited availability of evidence on the efficacy and safety of standard treatment regimens in older patients. At the root of this situation is the low rate of participation of older patients in clinical trials, often due to age limits for inclusion, and limitations on the participation of persons with significant comorbidities or organ dysfunction. Although this has begun to change in recent years, most agents currently in use have not been tested in a substantial number of older patients. This includes the targeted agents that have, in the last fifteen years, changed the prognosis of patients with early and advanced breast cancer. Most data guiding the use of targeted agents in older patients come from sub-analysis of larger trials or small retrospective cohort studies. The goal of this review is to go over the available evidence regarding the efficacy and safety of targeted agents approved for use in breast cancer (trastuzumab, lapatinib, T-DM1, pertuzumab, neratinib, palbociclib, bevacizumab, ribociclib, abemaciclib, everolimus, olaparib, talazoparib), and place their side effects into an older-specific context in order to help medical oncologists when making treatment decisions and managing older patients with breast cancer.
- Overall Survival with Ribociclib plus Endocrine Therapy in Breast Cancer. [Journal Article]
- NEJMN Engl J Med 2019 Jun 04
- CONCLUSIONS: This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
- Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. [Journal Article]
- CBClin Breast Cancer 2019 Feb 28
- CONCLUSIONS: In the US subset of MONALEESA-2, ribociclib with letrozole showed superior efficacy versus letrozole alone. These findings are consistent with the global population and support first-line use of ribociclib with letrozole in patients with HR+/HER2- ABC.
- Intensive safety monitoring program of antineoplastic medicines: A pilot study in a Portuguese oncology hospital. [Journal Article]
- JOJ Oncol Pharm Pract 2019 May 22; :1078155219849277
- CONCLUSIONS: This intensive safety monitoring program was feasible and allowed identifying serious and unexpected adverse drug reactions, adding value to pharmacovigilance and therefore contributing to improve patient safety. Further research is needed to confirm the findings of this pilot study.
- The Role of CDK4/6 Inhibitors in Breast Cancer. [Review]
- CTCurr Treat Options Oncol 2019 May 18; 20(6):52
- Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer.…
Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40-45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.
- Concurrent radiotherapy with palbociclib or ribociclib for metastatic breast cancer patients: Preliminary assessment of toxicity. [Journal Article]
- BBreast 2019 May 08; 46:70-74
- CONCLUSIONS: concomitant treatment of CDK4/6 and radiotherapy seems well tolerated; high grade hematological toxicity is common, but did not change treatment course in the majority of patients. Previous toxicity should be carefully evaluated as it usually reoccurs.
New Search Next
- Streamlined Synthesis of Diaminopyridines by Pd-Catalyzed Ammonia Coupling with Deactivated Amino-Chloropyridines. [Journal Article]
- CChemistry 2019 May 13
- An efficient and cost-effective two-step synthesis of diaminopyridines, fundamental building blocks of biologically active compounds, is reported. The advantages over previously reported routes inclu…
An efficient and cost-effective two-step synthesis of diaminopyridines, fundamental building blocks of biologically active compounds, is reported. The advantages over previously reported routes include cost and wider availability of the bromo-chloropyridine starting materials and the straightforward accessibility to an extended array of diaminopyridine regioisomers. The key enabler of this synthetic strategy is the development of an unprecedented palladium-catalyzed coupling reaction of ammonia with chloropyridines deactivated by the presence of an alkylamino substituent. The coupling reaction was accomplished with very low catalyst loadings under remarkably mild reaction conditions, making the system particularly suitable for both academic and industrial applications. The utility of this methodology is exemplified by the application to the synthesis of highly relevant scaffolds, including the synthetic intermediates of the marketed drugs Ribociclib and Palbociclib.