INTRODUCTION TO CYCLIBTOOL V2.0

Where does the Cyclibtool platform come from?

The Cyclibtool website was launched in November 2020.  The tool was initially based in our manuscript “palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication“ 1 ( click here   to view ) published in May 2019, but with some enhancements made to the tables displaying specific drug-drug interactions (DDIs) and the inclusion of DDIs for abemaciclib, which was later approved in Spain .

Our main objectives were:

1. To comprehensively inform professionals about the specific drug-drug interactions (DDIs) associated with the three globally aproved cyclin-dependent kinase 4/6 inhibitors (CDK4/6i): palbociclib, ribociclib, and abemaciclib, and by what mechanism they occur.
2. To provide a final assessment categorized by a color-coded system, similar to a high-light: 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 is strong and the combination should be avoided.
3. To offer a list of alternative drugs that can be safely prescribed in the event of identified DDIs. This aspect has been always essential in our project.

To classify the DDIs, we used the following premises:

 • palbociclib acts as both a substrate and a weak inhibitor of CYP3A4. Caution should be exercised with sensitive substrates of membrane transporters. No significant risk of QTc prolongation has been reported.

• ribociclib is a substrate of CYP3A4 and also exhibits CYP3A4 inhibitory activity (moderate inhibition at 400mg, strong inhibition at 600mg). Caution should be exercised with sensitive substrates of membrane transporters. Treatment with ribociclib carries a potential risk of Torsade de Pointes, indicating a weak evidence of QTc prolongation when taken at recommended doses.

 • abemaciclib acts as a substrate of CYP3A4 but does not induce or inhibit this enzymatic complex. It has not been associated with QTc prolongation. Caution should be exercised with sensitive substrates of certain membrane transporters. Furthermore, it also highly bound to plasma proteins and caution should be exercised when combining it with other drugs that also have high protein binding.

Why a new Cyclibtool? What has changed?

After the excellent reception of our Cyclibtool by oncologists, pharmacists and other Health professionals, in many countries around the world, and being aware that any online tool requires updating, the SOLTI group decided in 2023 to prepare a new version, expanded to include more drugs, dynamic in nature, multilingual and in a format more in line with current times. Additionally, after conducting a usability test of our first version with oncologists of different ages and different levels of familiarity with the tool. We realized that the table-based format of the initial version, with some repetitions of the drugs to be checked, could occasionally lead to errors, which we wanted to avoid. The appearance of Cyclibtool version 2.0 has changed, along with the method of inquiring about each drug, while maintaining alignment with our longstanding goals and consistent premises for assessing DDIs. We have also retained the original Supplementary Section, which includes an overview of metabolism (Annex 1, click here   to view) and the incidence and management of abemaciclib toxicity (Annex 2, click here   to view), as our original article only focused on palbociclib and ribociclib, as previously mentioned. Additionally, an updated version of the Summary of Product Characteristics for palbociclib ( click here ), ribociclib ( click here ), and abemaciclib ( click here ) is available

Specifically, the changes made in comparison with the first version are detailed below, along with the methodology followed in this updated Cyclibtool:

• First and foremost, unlike its predecessor, which relied on drug tables, the new version  is based on Artificial Intelligence Technology and uses a format of interactive c.
• The selection of drugs included was based on the classification provided by the Anatomical Therapeutic Chemical (ATC) Classification 2 . The decision to include or exclude certain groups of drugs relied on pragmatic criteria and was made consensually by a team consisting of 1 oncologist, 5 pharmacists, and 2 members of the SOLTI office. Topical dermatological drugs, antiparasitic products, medications exclusively used in emergencies or life-threatening situations, and some endocrine treatments not recommended in breast cancer patients (e.g., hormone replacement therapy compounds) were excluded.
• The number of drugs included has been expanded, increasing from 200 to 715 in total. Additionally, the DDIs for the drugs included in the first version have been reviewed, particularly taking into account any potential changes in the AZCERT classification regarding Torsade de Pointes risk 3 . Overall, the number of drugs incorporated has increased for nearly all drug families, except for the Complementary Alternative Medicine (CAM) category, which will be updated in a next future.
• Regarding ribociclib specifically, given the dose-dependent  variability in the severity of its drug-drug interactions (DDIs) in terms of QTc prolongation and CYP3A4 inhibition,and considering the disparity in initial doses between the metastatic context (600mg) and the adjuvant setting where it is likely to be approved (400mg), we deemed appropriate to assess DDIs for each of these two dose levels of ribociclib, a step that was not undertaken in the initial version. This distinction between dose levels was not extended to palbociclib or abemaciclib, as their inhibition of CYP3A4 was weak or non-existent, respectively, and neither drug is associated with QTc interval prolongation.
• To keep the website updated and to address discrepancies from users regarding the evaluation of DDIs, a suggestion box can be accessed located at the suggestions section, and it will be answered quarterly. Similarly, potential changes in the AZCERT’s classification 3  will be reviewed quarterly, and the inclusion of new drugs deemed clinically relevant will be considered.

How to use the new Cyclibtool

The operation of the new Cyclibtool is highly intuitive. Through an interactive chat, it will guide you in the search you want to perform.

• To begin, the tool will ask you which CDK4/6 inhibitor you want to use and then prompt you to enter the drug for which you want to check the DDIs.
• Afterward, it will present you with an assessment of the potential interaction; similarly to the first version, safe concomitant administration will be highlighted in green, caution in orange, and contraindication in red. In the latter two situations, the tool will provide an explanatory phrase detailing the mechanism behind the DDIs. It will then inquire whether you want it to provide a list of the therapeutic alternatives within the same drug family (not beyond category 3 of ATC classification). It should be mentioned that the list may include drugs with different pharmacological activities and indications. Therefore, as with our first version, their selection is at the discretion of the user and is outside the scope of Cyclibtool.
• Cyclibtool operates in a binary manner. This means that it cannot answer multiple questions at once, so it is not possible to inquire about which CDK4/6i the drug interacts with. Instead, the user must proceed to ask about DDIs with palbociclib, ribociclib, and abemaciclib successively. This also helps to prevent interpretation errors.

Next steps

In the coming months, we will continue working on Cyclibtool v2.0. We aim to expand the CAM section. However, we anticipate that this will be a challenging task due to the limited evidence regarding the pharmacological properties and DDIs of these compounds.

On the other hand, we are exploring the possibility of presenting equivalent doses, or alternatively, initial, maintenance, and maximum doses, for certain drug families with frequent DDIs, such as opioid analgesics, antidepressants, and lipid-lowering agents, among others.

Acknowledges

The new version of Cyclibtool is the culmination of the efforts of five highly specialized pharmacists in the field of drug interactions: Carolina Valdivia, Pablo Sánchez, Berta Renedo, and Cristina Fernández, alongside Faten Ahmad. Faten has played a pivotal role in coordinating the selection, distribution, and review processes of therapeutic compounds, while also establishing consistent criteria for evaluating DDIs. I extend my deep gratitude to all of them for the professionalism, commitment, and enthusiasm they have put into this project. Additionally, I must acknowledge the tireless contributions of Helena Masanas and Albert Martínez from the SOLTI office. Last, but not least, gratitude is also extended to Mashup Media, as well as Novartis, Lilly, and Pfizer for their sponsorship. We all share the same desire: for Cyclitool v2.0 to be useful and facilitate the work of healthcare professionals, including oncologists, physicians from various specialties, pharmacists, and nurses, in their daily commitment to caring for cancer patients.

Dr. Meritxell Bellet
Medical Oncologist
Member of the Executive Board of SOLTI

Barcelona, may 2024

References

1. 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.
2. Norwegian Institute of Public Health. ATC/DDD Index 2024. Available at: https://atcddd.fhi.no/atc_ddd_index/ . Consultation date: may 2024.
3. CredibleMeds. Available at: https://www.crediblemeds.org . Consultation date: may 2024.