Polypharmacy and drug-drug interactions in metastatic breast cancer patients receiving cyclin-dependent kinase (CDK) 4/6 inhibitors

Abstract

Introduction

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly changed the treatment strategy for patients with locally advanced or metastatic hormone receptor positive (HR+), human epidermal growth factor 2 negative (HER2) breast cancer. The purpose of the study was to determine the prevalence of drug-drug interactions (DDI) in breast cancer patients using CDK 4/6 inhibitors and the extent of DDI reflected in the clinic and to increase clinical awareness among physicians.

Method

The data of 115 metastatic breast cancer patients using CDK 4/6 inhibitors who were admitted to the Medical Oncology outpatient clinic between July 2021 and July 2023 were retrospectively reviewed. The Drugs.com® Drug Interaction Checker application was used for the interaction between the CDK 4/6 inhibitor and other drugs.

Results

Among patients included in the study, 97.3% had at least one additional drug use. We have identified a total of 170 potential DDI risks in 63.5 % of patients. Among these, 50.5% had a major potential DDI. In our study, there was a potential risk of QT prolongation in 45.2% of 170 DDI, an increase in the potential toxicity of the additional drug in 44.1%, an increase in the potential toxicity of the CDK 4/6 inhibitor in 5.3%, a decrease in the potential efficacy of the CDK 4/6 inhibitor in 2.9%, a decrease in the potential efficacy of the additional drug in 1.1%, and a serious potential infection risk in 1.1%. Most of the drug interactions were QT prolongation and increased toxicity of the additional drug. In terms of cardiovascular events, grade-2 and grade-3 QTc prolongation was found in 4.3% and 1.7% of these interactions, respectively. When evaluated in terms of CDK 4/6 inhibitor subtype, there was a potential risk of DDI at major level with Ribocilib and at moderate level with Palbociclib.

Conclusion

If CDK 4/6 inhibitors interact with concomitant drugs, they may cause an increase in the incidence of cardiac side effects and a decrease in the effect of the CDK 4/6 inhibitor or additional drug or an increase in toxicity. Increasing awareness of this issue will help to reduce the rates of side effects or toxicity and provide effective antitumour therapy.

Keywords

Drug-drug interaction QT prolongation Ribociclib Palbociclib Cyclin-dependent kinase (CDK) 4/6 inhibitors

Introduction

Cyclin-dependent kinases (CDKs) are critical regulatory enzymes that manage cell cycle transitions and eventual cell division. Selective inhibition of CDK 4/6 causes cell cycle arrest from G1 or G2/M phase, resulting in reduced cell viability and tumoural growth.¹ There are currently three different CDK 4/6 inhibitors in use, ribociclib, pablociclib and abemaciclib, which are approved by the Federal Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of patients with HR + and HER2− locally advanced or metastatic breast cancer in combination with specific endocrine therapies.² HR + and HER2− are the most common breast cancer subtypes and antiestrogen therapy remains the therapeutic centrepiece of treatment in these patients. Although initial hormone therapy is effective, about half of patients with HR + advanced breast cancer develop resistance to antiestrogen therapies at some point in their lives. This leads to recurrence of the disease and limited clinical benefit.³ Landmark CDK 4/6 inhibitor trials have demonstrated that the use of antiestrogen therapies in combination with CDK 4/6 inhibitors significantly improves the outcomes of patients with HR + locally advanced or metastatic breast cancer compared to the use of antiestrogen therapies alone.^4–8 All CDK 4/6 inhibitors are orally administered; therefore, they are more practical than other invasive treatment modalities and provide a significant advantage in terms of quality of life.

Drug interactions are classified as pharmacokinetic and pharmacodynamic interactions. Pharmacokinetic drug interaction refers to changes in drugs at the level of absorption, distribution, metabolism and elimination. Pharmacodynamic interaction refers to the interaction in which one active compound changes the pharmacological effect of another. This effect may be synergistic, additive or antagonistic.⁹ When CDK 4/6 inhibitors were administered with other drugs, the oral bioavailability or tissue/plasma distribution of CDK 4/6 inhibitors may increase or decrease. This may lead to a reduction in the expected benefit of CDK 4/6 inhibitors or to the development of serious toxicities.¹⁰ The pharmacokinetic profiles of all three CDK 4/6 inhibitors in use are similar and all three are metabolised mainly by CYP3A4 after rapid absorption and distribution.¹¹ Therefore, it is always possible that another drug administered concomitantly with a CDK 4/6 inhibitor may affect the metabolism of CDK 4/6 inhibitors via the CYP3A4 isozyme or drug bioavailability via gastrointestinal absorption. The incidence of chronic diseases increases with the risk of cancer, which increases with age, and this leads to the use of multiple medications.¹² In addition, the use of additional drugs becomes mandatory for the prevention of side effects secondary to symptomatic or anti-cancer drugs in cancer patients. All these factors increase the risk of drug-drug interactions (DDI) in cancer patients. The purpose of this study was to determine the prevalence of potential DDI in breast cancer patients using CDK 4/6 inhibitors and the extent of DDI reflected in the clinic and to raise awareness among physicians.

Material and method

Study population

Patients with locally advanced or metastatic HR+, HER2− breast cancer using CDK 4/6 inhibitors who were admitted to the Medical Oncology outpatient clinic between July 2021 and July 2023 were included in the study. The study included 115 female patients. Data on oncological diagnosis, prescribed CDKs, age, gender, electrocardiogram data taken during treatment for corrected QT prolongation risk and comorbidities were collected from patient files. In the electronic prescription system, all drugs prescribed to patients by oncologists or other branch physicians during the use of CDK 4/6 were recorded.

Potential CDK 4/6 inhibitors-drug interactions

The Drugs.com® Drug Interaction Checker application was used for the interaction between CDK 4/6 inhibitors and other drugs.¹³ The severity of drug interaction was classified as minor, moderate and major. Detailed information about DDI severity is shown in Table 1. The drugs interacting with CDK 4/6 inhibitors were grouped as ‘opioid pain medications, antiemetics, antibiotics, anti-psychotics, cardiovascular and dyslipidaemia drugs and others’.

Table 1.

Drug interactions severity definitions.

Level of severity	Description
Major	Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate	Usually avoid combinations; use it only under special circumstances.
Minor	Minimise risk; assess risk and consider an alternative drug.

Calculation and classification of corrected QT interval (QTc) in patients using CDK 4/6 inhibitors

Bazett's formula (QTc = QT / √RR) was used for QTc calculation.

Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 was used for QTc classification.

Normal prolongation: QTc < 450 ms

Grade 1: QTc 450–480 ms

Grade 2: QTc 481–500 ms

Grade 3: QTc ≥501

Grade 4: Torsades de pointes; polymorphic ventricular tachycardia

Statistical analysis

SPSS 27.0 programme was used for statistical analysis of the results obtained. The Kolmogorov–Smirnov test was used to analyse normality. For descriptive analysis, categorical variables were defined as frequency and distributions with percentages, and quantitative variables were presented as median, minimum and maximum values.

Results

Baseline characteristics associated with patient and drugs

This study included 115 female patients with metastatic HR+, HER2− breast cancer. The mean age of all patients was 58 ± 12 years (range, 30–86). Among the chronic diseases, 23.5% of the patients had hypertension, 14.8% had diabetes mellitus, 13% had depression, 7.8% had asthma/COPD, 6.9% had cardiovascular disease, 6.1% had dyslipidaemia and 5.2% had rare diseases.

The median number of drug use was 8 (range, 0–25) and the median number of potential DDIs was 1 (range, 0–10). In 97.3% of the patients, there was at least one additional drug use together with CDK 4/6 inhibitor. At least one DDI risk was detected in 63.5% of the patients. In two patients, the use of 10 drugs interacting with CDK 4/6 inhibitor was detected. Ribociclib and Palbociclib were used by 73% and 27% of the patients, respectively. A total of 43 potential drug interactions were identified. Considering that the same drug was used in more than one patient, a total of 170 potential DDI risks were identified. Among these 170 interactions detected, 50.5% had a major interaction risk, 46.5% had a moderate interaction risk and 2.9% had a minor interaction risk. In terms of interaction frequency, 45.2% had prolongation of QT, 44.1% had potential increase in toxicity of the additional drug, 5.3% had potential increase in toxicity of the CDK 4/6 inhibitor, 2.9% had potential decrease in efficacy of the CDK 4/6 inhibitor, 1.1% had potential decrease in efficacy of the additional drug and 1.1% had serious potential infection risk. Patient and DDI-related baseline characteristics are shown in Table 2.

Table 2.

Baseline characteristics associated with patient and drugs.

		Mean ± SD	Min–Max
Age (year)		58 ± 12	30–86
		N	%
Comorbidity	Hypertension	27	23.5
	Diabetes mellitus	17	14.8
	Depression	15	13
	Asthma/COPD	9	7.8
	Cardiovascular disease	8	6.9
	Dyslipidaemia	7	6.1
	Other diseases	6	5.2
		Median	Min–Max
Average number of drugs taken		8	0-25
Number of drug interaction		1	0-10
		N	%
Concomitant medication	Yes	112	97.3
Concomitant medication	No	3	2.6
Cyclin-dependent kinase inhibitor subtype	Ribociclib	84	73.0
Cyclin-dependent kinase inhibitor subtype	Palbociclib	31	27.0
Drug interactions severity	Major	86	50.5
	Moderate	79	46.5
	Minor	5	2.9
Potential interaction event frequency	L-QT-S	77	45.2
	IPCSD	75	44.1
	IPCFD	9	5.3
	DPCFD	5	2.9
	DPCSD	2	1.1
	Infection	2	1.1
Clinical consequences of QTc (ms)	Normal QTc	33	28.6
	Grade 1 QTc	14	12.1
	Grade 2 QTc	5	4.3
	Grade 3 QTc	2	1.7
	N/A	23	20
Total drug interactions	Yes	73	63.5
	1 < DI	54	46.9
	1 = DI	19	16.5
	No	42	36.5

QTc: corrected QT interval; L-QT-S: long QT syndrome; IPCSD: increase in plasma concentration of the second drug; IPCFD: increase in plasma concentration of first drug; DPCFD: decrease in plasma concentration of first drug; DPCSD: decreased plasma concentration of the second drug; COPD: chronic obstructive pulmonary disease; Min: minimum; Max: maximum; SD: standard deviation; N/A: not available; ms: millisecond. Italics emphasize that nearly half of the patients (n=54; 46.9%) have at least two DDIs.

In terms of the prevalence of corrected QT prolongation, grade 1 QTc prolongation (450–480 ms) was detected in 12.1%, grade 2 QTc prolongation (481–500 ms) in 4.3% and grade 3 QTc prolongation (>500 ms) in 1.7% of all DDI. QTc prolongation was not observed in 28.6% and electrocardiogram data were not available in 20% of the patients (Table 2).

Drugs interacting with CDK inhibitors and their frequency distribution

When evaluated in terms of CDK 4/6 inhibitor subtype, it was observed that 31 of the 43 additional drugs potentially had the risk of interaction only with Ribociclib, 1 had the risk of interaction only with Palbociclib, and 11 had the risk of interaction with both Ribociclib and Palbociclib. In addition, in terms of drug interaction severity, concomitant use of additional drugs with Ribociclib was found to carry a higher risk of major drug interaction than concomitant use with Palbociclib.

When the amount of QTc prolongation and associated concomitant medication were analysed from the electrocardiogram data of the patients during the treatment period, grade 2 QTc prolongation was found in one patient receiving tramadol, one patient receiving granisetron, one patient receiving escitalopram, one patient receiving quetiapine and one patient receiving hydroxyzine. In addition, grade 3 QTc prolongation was found in one patient receiving tramadol and one patient receiving ondansetron. The distributional characteristics of the drugs at risk of potential interaction with CDK 4/6 inhibitors and the details related to the extent reflected in the clinic are given in Table 3.

Table 3.

Drugs interacting with cyclin-dependent kinase (CDK) inhibitors and their distribution features.

		Interaction event N (%)	RibociclibN (%)	RibociclibDI event	Ribociclib DI severity	Pablociclib N (%)	Pablociclib DI event	Pablociclib DI severity	Clinical outcomes of QT prolongation N (%)
Most commonly used additional drug group	Additional drug	170 (100)	133 (78.2)			37 (21.7)			Grade 1	Grade 2	Grade 3
Opioid pain medications	Tramadol	29 (25.2)	19 (16.5)	L-QT-S	Major	10 (8.6)	IPCSD	Moderate	5 (4.3)	1 (0.9)	1 (0.9)
	Fentanyl	11 (9.6)	9 (7.8)	IPCSD	Major	2 (1.7)	IPCSD	Moderate
	Oxycodone	5 (4.3)	5 (4.3)	IPCSD	Major	0 (0)	IPCSD	Moderate
Antiemetics	Granisetron	15 (13.0)	15 (13.0)	L-QT-S	Major	0 (0)	NI		6 (5.2)	1 (0.9)
	Dexamethasone	11 (9.6)	6 (5.2)	DPCFD	Moderate	5 (4.3)	DPCFD	Moderate
	Ondansetron	7 (6.1)	7 (6.1)	L-QT-S	Major	0 (0)	NI				1 (0.9)
Antibiotics	Ciprofloxacin	7 (6.1)	2 (1.7)	L-QT-S	Major	5 (4.3)	IPCFD	Moderate	2 (1.7)
	Metronidazole	6 (5.2)	6 (5.2)	L-QT-S	Moderate	0 (0)	NI		2 (1.7)
	Clarithromycin	6 (5.2)	5 (4.3)	L-QT-S	Moderate	1 (0.8)	IPCFD	Major
	Levofloxacin	2 (1.7)	2 (1.7)	L-QT-S	Major	0 (0)	NI		2 (1.7)
Anti-psychotics	Escitalopram	11 (9.6)	7 (6.1)	L-QT-S	Major	4 (3.5)	IPCSD	Minör	5 (4.3)	1 (0.9)
	Quetiapine	4 (3.5)	3 (2.6)	L-QT-S	Major	1 (0.8)	IPCSD	Moderate		1 (0.9)
	Venlafaxine	3 (2.6)	0 (0)	IPCSD	Moderate	3 (2.6)	IPCSD	Moderate
	Hydroxyzine	2 (1.7)	2 (1.7)	L-QT-S	Major	0 (0)	NI		1 (0.9)	1 (0.9)
	Mirtazapine	2 (1.7)	0 (0)	IPCSD	Moderate	2 (1.7)	IPCSD	Moderate
Cardiovascular and dyslipidaemia drugs	Amlodipine	7 (6.1)	7 (6.1)	IPCSD	Moderate	0 (0)	NI
	Atorvastatin	6 (5.2)	6 (5.2)	IPCSD	Moderate	0 (0)	IPCSD	Moderate
	Rosuvastatin	3 (2.6)	3 (2.6)	IPCSD	Moderate	0 (0)	NI
	Apixaban	2 (1.7)	0 (0)	IPCSD	Moderate	2 (1.7)	IPCSD	Moderate
Single drugs of the group	Metformin	4 (3.5)	4 (3.5)	IPCSD	Moderate	0 (0)	NI
	Mg sulfate	2 (1.7)	2 (1.7)	Aritmi	Moderate	0 (0)	NI
	Denosumab	2 (1.7)	1 (0.8)	Infection	Moderate	1 (0.8)	Infection	Moderate
	Sennoside	2 (1.7)	2 (1.7)	Arrhythmia	Moderate	0 (0)	NI
	Formoterol	2 (1.7)	2 (1.7)	L-QT-S	Major	0 (0)	NI		2 (1.7)
Others (DI = 1)	Single ones ^a	19 (16.5)	18 (15.6)			1 (0.8)

Ms: millisecond; Mg: magnesium; NI: no interactions; DI: drug interactions; first drug: CDK4/6 Inh; second drug: additional drug; L-QT-S: long QT syndrome; DPCFD: decrease in plasma concentration of first drug; IPCFD: increase in plasma concentration of first drug; DPCSD: decreased plasma concentration of the second drug; IPCSD: increase in plasma concentration of the second drug.

Verapamil, olanzapin, metilprednisolon, salmoterol, donepezil, alprazolam, prednisolon, moksifloksasin, ivadrabin, risperidon, aprepitant, budesonid, buspiron, oksibutinin, aripiprazol, mirabegron, sülprid, famotidin, olanzapine.

It was observed that opioid analgesics were used most frequently as a group among CDK 4/6 inhibitors and drugs with a potential risk of DDI. In this group, tramadol (25.2%) and fentanyl (9.6%) were used most frequently. The second most frequently used drug group with other potential DDI risk was antiemetics. Granisetron (13%) and dexamethasone (9.6%) were the two most preferred drugs. Afterwards, it was observed that escitalopram (9.6%) among antipsychotics, ciprofloxacin (6.1%) among antibiotics, amlodipine (6.1%) among cardiovascular drugs and metformin (3.5%) among anti-diabetic drugs were frequently used among drugs with potential DDI risk. The frequency of use of CDK 4/6 inhibitors and drugs with potential DDI risk is given graphically in Figure 1.

Discussion

Polypharmacy may limit the therapeutic value of medicines prescribed for the primary disease, leading to a potential risk of DDI. Especially in cancer patients, DDI is becoming more and more important in terms of efficacy, safety and cost of treatment. Although there are many studies in the literature on DDI involving classical chemotherapy drugs together with other oral anti-cancer drugs, there are a limited number of studies, mostly presented as case reports, emphasising DDI involving CDK 4/6 inhibitors.^14–20

In this study, we evaluated the prevalence of potential DDI associated with CDK 4/6 inhibitors, the expected effect, the severity of effect and the significance of this interaction. We also evaluated the relationship between drug interactions and QT-interval prolongation. In our cohort, 97.3% of patients had at least one additional drug use. We have identified a total of 170 potential DDI risks in 63.5% of patients, of which 50.5% had a potential risk of major DDI. When evaluated in terms of CDK 4/6 inhibitor subtype, there was more major potential interaction risk with Ribocilib and more moderate potential interaction risk with Palbociclib. In terms of pharmacokinetic changes, it is known that Ribociclib is metabolised by CYP3A4 enzyme and Palbociclib is metabolised by both CYP3A4 and SULT2A1 enzymes.¹⁰ The fact that plabociclib is also metabolised by the SULT2A1 enzyme caused these two agents to show large differences in terms of DDI patterns.

In our study, 45.2% of 170 DDIs had a potential risk of QT prolongation, 44.1% had a potential increase in the toxicity of the additional drug, 5.3% had a potential increase in the toxicity of CDK 4/6 inhibitor, 2.9% had a potential decrease in the efficacy of CDK 4/6 inhibitor, 1.1% had a potential decrease in the efficacy of the additional drug, and 1.1% had a serious potential risk of infection. Most of the drug interactions were associated with potential QT prolongation and potential increase in toxicity of the additional drug.

Myocardial dysfunction or arrhythmias may be common in patients with locally advanced or metastatic breast cancer as a result of prior exposure to cardiotoxic chemotherapies.²¹ Concomitant use of more than one drug that prolongs QT further increases this risk. In our study, a potential risk of QT prolongation via Ribociclib-associated DDI was found with a high rate of 45.2%. When the actual clinical effects of this situation in our patient population were analysed, it was observed that 4.3% of all interactions resulted in grade 2 and 1.7% in grade 3 QTc prolongation. Therefore, in the MONALEESA 2, MONALEESA 3 and MONALEESA 7 studies, which are the turning point for CDK 4/6 inhibitors, grade 2 QTc prolongation was found in 3.6–6% and grade 3 QTc prolongation in 0.6–1%, which supports the actual clinical results of our study.^{7, 8, 22} In addition, since the potential risk of QT prolongation due to DDI associated with Palbociclib is as low as possible, Palbociclib has not been described in detail in this regard.

Pain is a common symptom in patients with advanced breast cancer²³ and opioid analgesics are widely used in this context. In the literature, there are studies emphasising that tramadol may cause hepatotoxic effects associated with the use of high doses.²⁴ Among all drugs that interacted with CDK 4/6 inhibitors in our patient group, tramadol was the most frequently prescribed drug with a rate of 25.2%. It was also observed that fentanyl and oxycodone were prescribed at a rate of 9.6% and 4.3%, respectively. In the electrocardiogram follow-up of our patients, grade 2 QTc prolongation was detected in one patient who received tramadol and grade 3 QTc prolongation was detected in another patient. No prolongation of QTc above the reference value was detected in patients using fentanyl or oxycodone as reflected in the clinic. Especially caution should be exercised with regard to the potential risk of QT prolongation that may develop in the concomitant use of these three agents with Ribociclib and the potential risk of toxicity that may develop in the concomitant use of these three agents with Palbociclib.

Another frequently prescribed drug group in cancer patients is anti-emetic drugs. In our patient group, granisetron and ondansetron were found to have a potential risk of DDI with high rates of 13% and 6.1%, respectively. When the drug information is analysed, it is stated that these two drugs, which do not interact with Palbociclib, carry a major potential risk of QT prolongation when used with Ribociclib.²⁵ In fact, QTc prolongation at grade 2 level was detected in one patient using granisetron in our patient group. The use of dexamethasone, which has a usage rate of 9.6% among DDI and can also be preferred as an anti-emetic, was found to carry a moderate risk of potential decrease in the efficacy of both Ribociclib and Palbociclib.¹³

Another group of drugs that we often have to use in cancer patients are antibiotics. In our cohort, antibiotics constituted 18.2% of drug interactions. When the literature was reviewed, it was emphasised that clarithromycin and quinolone should be avoided especially in terms of the risk of torsades de pointes that may develop with QT prolongation in concomitant use with CDK 4/6 inhibitors.²⁶ Grade 1 QTc prolongation was detected in a total of six patients, two receiving ciprofloxacin, two receiving metronidazole and two receiving levofloxacin. Therefore, clinicians should pay exercise caution using antibiotics in patients with metastatic breast cancer using CDK 4/6 inhibitors due to possible toxicities.

Depression and anxiety disorders are common in cancer patients.²⁷ Studies have emphasised that escitalopram, which is frequently preferred in this group, may cause QT prolongation and torsades de pointes, especially at therapeutic doses.^28,29 In our cohort, antipsychotics accounted for 19.1% of drug interactions. Within this group, escitalopram was responsible for 9.6% of all DDIs. Grade 2 QTc prolongation was detected in a total of three patients, one receiving quetiapine, one receiving escitalopram and one receiving hydroxyzine. Close electrocardiogram and electrolyte monitoring should be carried out in case of initiation of any medication with such a potential risk of effects.

Drug interactions are also important in breast cancer patients with chronic diseases such as diabetes, hypertension and hyperlipidemia. In our cohort, statins were responsible for 11.3% of potential DDI. In the literature, there are case-based studies emphasising the toxicity of statins in combination with CDK 4/6 inhibitors. Cases of rhabdomyolysis have been described especially in the concomitant use of Ribociclib and Palbociclib with simvastatin.^{18, 19} Regarding metformin, one of the anti-diabetic drugs, there is a single case report in the literature highlighting the development of lactic acidosis when used together with Ribociclib.²⁰ It is important to monitor muscle-specific creatinine kinase and lactic acid levels in these drug combinations.

The limitations of our study are that it was retrospective, potential drug interactions were analysed using drug interaction checker software, all clinical toxicities were not followed prospectively and electrocardiogram data were missing in some patients after the first 2 months from the start of treatment. The strength of the study is that it is the first study to give regarding the potential for QT prolongation in patients receiving CDK 4/6 inhibitors and additional drug. Moreover, it is also the first study to raise awareness about DDI in patients receiving CDK 4/6 inhibitor and additional drug.

Conclusion

CDK 4/6 inhibitors are frequently used in oncological practice. Oral drug administration may seem advantageous, but long-term use increases the potential risk of DDI. Therefore, doctors prescribing CDK 4/6 inhibitors should be alert about DDI, including QT prolongation, the increase or decrease in plasma concentration of CDK 4/6 inhibitors or additional drugs. Since there are few data on DDI with CDK 4/6 inhibitors in the literature, we think that our study will make an important contribution to the literature.

Footnotes

Author contributions

TK and GUE researched literature and conceived the study. NB wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The protocol for sample collection was approved by the Basaksehir Cam and Sakura City Hospital Ethics Committee and was carried out according to the requirements of the Declaration of Helsinki.

ORCID iD

Tanju Kapagan

References

Asghar

Witkiewicz

Turner

, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov 2015; 14: 130–146.

Chen

, et al. Latest overview of the cyclin-dependent kinases 4/6 inhibitors in breast cancer: the past, the present and the future. J Cancer 2019; 10: 6608–6617.

Razavi

Chang

, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell 2018; 34: 427–438.

Sledge

Toi

Neven

, et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2− advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017; 35: 2875–2884.

Gelmon

Walshe

Mahtani

, et al. Efficacy and safety of palbociclib in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with preexisting conditions: a post hoc analysis of PALOMA-2. Breast 2021; 59: 321–326.

Cristofanilli

Turner

Bondarenko

, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016; 17: 425–439.

Hortobagyi

Stemmer

Burris

, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol 2018; 29: 1541–1547.

Slamon

Neven

Chia

, et al. Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival. Ann Oncol 2021; 32: 1015–1024.

Tan

Clewell

Campbell

, et al. Evaluating pharmacokinetic and pharmacodynamic interactions with computational models in supporting cumulative risk assessment. Int J Environ Res Public Health 2011; 8: 1613–1630.

10.

Spring

Zangardi

Moy

, et al. Clinical management of potential toxicities and drug interactions related to cyclin-dependent kinase 4/6 inhibitors in breast cancer: practical considerations and recommendations. Oncologist 2017; 22: 1039–1048.

11.

Braal

Jongbloed

Wilting

, et al. Inhibiting CDK4/6 in breast cancer with Palbociclib, Ribociclib, and Abemaciclib: similarities and differences. Drugs 2021; 81: 317–331.

12.

Dovjak

. Polypharmacy in elderly people. Wien Med Wochenschr 2022; 172: 109–113.

13.

Report DI. Drugs.com® [Internet]: Available from: https://www.drugs.com/interactions-check.php?drug_list=3790-0,2221-0 (2023, accessed 13.08.2023).

14.

Rassy

Bardet

Bougacha

, et al. Association of adherence to endocrine therapy among patients with breast cancer and potential drug-drug interactions. JAMA Netw Open 2022; 5: e2244849.

15.

Ramsdale

Mohamed

, et al. Polypharmacy, potentially inappropriate medications, and drug-drug interactions in vulnerable older adults with advanced cancer initiating cancer treatment. Oncologist 2022; 27: e580–e588.

16.

Ismail

Khan

, et al. Prevalence and significance of potential drug-drug interactions among cancer patients receiving chemotherapy. BMC Cancer 2020; 20: 35.

17.

Badran

Abu Amna

Turgeman

, et al. Rhabdomyolysis induced by the interaction between ribociclib and statins- case report and literature review. Breast Cancer (Dove Med Press) 2023; 15: 47–50.

18.

Nersesjan

Hansen

Krag

, et al. Palbociclib in combination with simvastatin induce severe rhabdomyolysis: a case report. BMC Neurol 2019; 19: 47.

19.

Streicher

Daulange

Madranges

, et al. Severe rhabdomyolysis induced by possible drug-drug interaction between ribociclib and simvastatin. J Oncol Pharm Pract 2021; 27: 722–726.

20.

Lagampan

Poovorawan

Parinyanitikul

. Lactic acidosis, a potential toxicity from drug-drug interaction related to concomitant ribociclib and metformin in preexisting renal insufficiency: a case report. Cancer Rep (Hoboken) 2022; 5: e1575.

21.

Martel

Maurer

Lambertini

, et al. Breast cancer treatment-induced cardiotoxicity. Expert Opin Drug Saf 2017; 16: 1021–1038.

22.

Tripathy

Colleoni

, et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol 2018; 19: 904–915.

23.

Khan

Ladha

Abdallah

, et al. Treating persistent pain after breast cancer surgery. Drugs 2020; 80: 23–31.

24.

Helmy

Abdalla

Abd El Rahman

, et al. Hepatotoxic effect of tramadol and O-desmethyltramadol in HepG2 cells and potential role of PI3 K/AKT/mTOR. Xenobiotica 2021; 51: 1029–1037.

25.

PDR Drug Information. Available at, https://www.pdr.net/drug-information/kisqali?druglabelid=24052 (accessed 18.08.2023).

26.

Bellet

Ahmad

Villanueva

, et al. Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication. MTher Adv Med Oncol 2019; 11: 175883591983386.

27.

Maass

Roorda

Berendsen

, et al. The prevalence of long-term symptoms of depression and anxiety after breast cancer treatment: a systematic review. Maturitas 2015; 82: 100–108.

28.

Zivin

Pfeiffer

Bohnert

. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry 2013; 170: 642–650.

29.

Alvarez

Vieira

Garcia-Moll

. Citalopram, escitalopram and prolonged QT: warning or alarm?. Rev Psiquiatr Salud Ment 2014; 7: 147–150.