Aims of the platform
Since the publication of our paper “Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication”1 in May 2019, some facts occurred that have prompted us to develop a web page/navigator based on the manuscript and to update some of the information include on it. These important facts are the following:
- Abemaciclib has been approved in Spain in 2019, therefore we consider necessary to add information about its toxicity and putative drug-drug interactions (DDIs).
- Additional publications regarding toxicities of palbociclib and ribociclib have been published and wider clinical experience is now available. In particular, one publication1 regarding a putative mechanism of QTc enlargement which is specific for ribociclib, but not for palbociclib, has led us to view our previous classification based on QTc risk as excessively conservative for palbociclib. On view of this new data, we have changed the categorization of risk for palbociclib where the DDIs described were based just on QTc enlargement.
- Our manuscript has elicited a substantial interest among Physicians according to Afimetrix Statistics. However, according to the feedback received, the length of the manuscript is felt to be excessive and time-consuming when checking a particular drug-drug interaction (DDI). The present web/navigator has been developed to address this issue, therefore facilitating the access to the information needed.
Taking into account all these three points, we have updated the DDIs and redistribute the information for the present web, but we maintain the original aims of our multidisciplinary Consensus, that were to inform physicians of the putative DDIs, their mechanism of action, and above all, to offer positive lists of drugs that can be safely administered in combination with CDK4/6 inhibitors (CDK 4/6i). In our knowledge, this is a feature unique of this web, unlike other DDIs checkers available online.
In this web, as in the original manuscript, the drugs of a certain family are classified in 3 categories, that mimics the colors of a traffic-light, depending of the risk of DDIs with CDK4/6i: Green: for safe drugs; Orange: for drugs that should be administered with caution in combination with a certain CDK4/6i; and Red: when the risk of DDIs is strong and the combination of a certain drugs should be avoided.
In our previous manuscript, the table which indicated the significance of the degree of induction/ inhibition of CYP3A4 according to palbociclib or ribociclib was unfortunately located in the Supplementary Material, and therefore, this information, very relevant in our view, could be unnoticed and lead to a wrong perception of homogenization of the DDIs via CYP3A4 between palbociclib and ribociclib. To solve this issue, a remainder of the degree of induction/inhibition with each CDK4/6i (abemaciclib added) and its consequences in terms of change of levels of concomitant drugs is always provided when it applies.
To classify the DDIs, we have considered the following premises:
- Palbociclib. It is both a substrate and a weak inhibitor of CYP3A4. Caution should be taken with sensitive substrates of membrane transporters*. No relevant risk of QTc enlargement is described.
- Ribociclib is a substrate of CYP3A4, and also a CYP3A4 inhibitor (moderate inhibition at 400mg, strong inhibition at 600mg). Caution should be taken with sensitive substrates of membrane transporters. Treatment with ribociclib entails a possible risk of Torsade de pointes2, which means that there is a weak evidence of QT enlargement when taken at recommended doses.
- Abemaciclib is a substrate of CYP3A4, but neither inducer nor inhibitor of this enzymatic complex. It has not been associated to QTc enlargement. Caution should be taken with sensitive substrates of certain membrane transporters.
*Details regarding specific DDIs of each compound with membrane transporters can be found in Background and Supplementary Material Section (to see, click here).
Since the original manuscript included information regarding pharmacokinetics and relevant toxicities only for palbociclib and ribociclib, now we generated a summary of abemaciclib metabolism and safety as well included in the Background and Supplementary Material section (to see, click here).
Last, but not least, our aim is to provide the professional with a dynamic and practical web which may include updates at regular bases (every 2 years), either incorporating new information about the three approved CDK4/6i (e.g. new formulations, etc) or the safety of administering each of them of new upcoming drugs or family of drugs.
Faten Ahmad, Hospital Pharmacist at the Unit for Coordination and Drug Strategy of the Catalan Institute of Health.
Meritxell Bellet, Medical Oncologist of the Breast Cancer Unit at Vall d’Hebron Hospital and Vall d’Hebron Institute of Oncology; SOLTI Governing Board Member.
- Bellet M, Ahmad F, Villanueva R, Valdivia C, Palomino-Doza J, Ruiz A, Gonzàlez X, Adrover E, Azaro A, Valls-Margarit M, Parra JL, Aguilar J, Vidal M, Martín A, Gavilá J, Escrivá-de-Romaní S, Perelló A, Hernando C, Lahuerta A, Zamora P, Reyes V, Alcalde M, Masanas H, Céliz P, Ruíz I, Gil M, Seguí MÀ, de la Peña L. Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. Ther Adv Med Oncol. 2019 May 10;11:1758835919833867. doi: 10.1177/1758835919833867. PMID: 31205497; PMCID: PMC6535716.
- Santoni M, Occhipinti G, Romagnoli E, Miccini F, Scoccia L, Giulietti M, Principato G, Saladino T, Piva F, Battelli N. Different Cardiotoxicity of Palbociclib and Ribociclib in Breast Cancer: Gene Expression and Pharmacological Data Analyses, Biological Basis, and Therapeutic Implications. BioDrugs. 2019 Dec;33(6):613-620. doi: 10.1007/s40259-019-00382-1. PMID: 31529317