The Pharmacological Profile of Cyclin-dependent Kinase (CDK) 4/6 Inhibitors: Clinical Management of Toxicity and Drug Interactions Related to CDK 4/6 Inhibitor-based Treatment in Advanced/Metastatic Breast Cancer
, , y | 05 abr 2020
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Article Category: Review Article
Publicado en línea: 05 abr 2020
Páginas: 2 - 14
Recibido: 12 may 2019
Aceptado: 07 oct 2019
DOI: https://doi.org/10.2478/fco-2019-0007
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© 2019 Tzelepi C. Vasiliki et al., published by Sciendo
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.
Monitoring of cdk4/6 inhibitors-associated adverse events.
| Shortness of breath, fatigue, increased tendency to bleed and/or bruise | Diarrhea, nausea, vomiting | Weight loss, jaundice, dark urine, itching, abdominal swelling | Cough, chest pain, shortness of breath, rapid breathing, rapid heart rate | Fainting episodes, palpitations | |
| Complete blood count | Electrolyte levels | Liver function tests | Monitoring of patients’ symptoms | ECG | |
| Cycles 1 and 2, 2 weeks after administration | 1 week after abemaciclib administration | During therapy | During therapy | First 4 weeks of treatment | |
| Fever, infections, Asian ethnicity, low baseline neutrophil count | Fever, dizziness, abdominal pain | Co-administration of other drugs | Deep vein thrombosis | Diarrhea, vomiting, co-administration of other drugs | |
| Day 1 of cycles 1 and 2, additional assessment during cycles 1 and 2 | During therapy | During therapy | During therapy | During therapy |
Potential drug-drug interactions with cdk4/6 inhibitors.
| Strong CYP3A | |||
| Antibiotics | Rifampin, rifabutin, rifapentine | Reduced exposure of CDK4/6 inhibitors | Avoid concomitant administration and consider alternative therapy |
| Anticonvulsants | |||
| Other | |||
| Strong CYP3A inhibitors | |||
| Antibiotics | Clarithromycin, telithromycin | Increased exposure of CDK4/6 inhibitors | Avoid concomitant administration and consider alternative therapy |
| Antifungals | |||
| Antiretrovirals, protease inhibitors | |||
| Other | |||
| Sensitive CYP3A substrates with a narrow therapeutic index | Midazolam, alfentanyl, fentanyl, cyclosporine, primozide, quinidine, dihydroergotamine, ergotamine, everolimus, sirolimus, tacrolimus | May result in increased exposure of concomitant agent | Close monitoring for signs of toxicity of the concomitant agent, modification of its dose as needed |
| QT-prolonging agents (only for ribociclib) | |||
| Antiarrhytmics | Amiodarone, disopyramide, procainamide, quinidine, sotalole | QTc prolongation and related consequences | Avoid concomitant administration |
| Other | |||
Clinical trials of cdk4/6 inhibitors in advanced and metastatic breast cancer.
| Phase II open-label | Postmenopausal, HR+ | 165 | 1st line | Palbociclib+letrozole versus letrozole alone | 20.2 versus 10.2 | 55 versus 39 | 81 versus 58 | - |
| Phase III placebo control | Postmenopausal, HR+/HER2−, ABC | 666 | 1st line | Palbociclib+letrozole versus letrozole alone | 24.8 versus 14.5 | 55 versus 44 | 85 versus 70 | - |
| Phase III placebo control | Pre-, peri-, postmenopausal, HR+/HER2−, ABC | 521 | 2nd line or later | Palbociclib+fulvestrant versus fulvestrant alone | 9.5 versus 4.6 | 25 versus 11 | 67 versus 40 | 34.9 versus 28.0 months |
| Phase III placebo control | Postmenopausal, HR+/HER2−, ABC | 668 | 1st line | Ribociclib+letrozole versus letrozole alone | 25.3 versus 16 | 53 versus 37 | 80 versus 73 | |
| Phase III placebo control | Postmenopausal, HR+/HER2−, ABC | 725 | 1st line or 2nd | Ribociclib+fulvestrant versus fulvestrant alone | 20.5 versus 12.8 | 40.9 versus 28.7 | - | - |
| Phase III placebo control | Pre-, perimenopausal HR+/HER2−, ABC | 672 | 1st line | Ribociclib+letrozole+goserelin versus letrozole+goserelin alone | 23.8 versus 13.0 | 51 versus 36 | 70.2% versus 46.0% at 42 months | |
| Phase II | HR+/HER2−, ABC | 132 | 3rd line or later | Abemaciclib 200 mg/12 h continuously | 6 | 20 | 42.4 | 17.7 months |
| Phase III placebo control | Pre-, peri-, postmenopausal, HR+/HER2−, ABC | 669 | Progress during neoadjuvant/adjuvant ET < 12 months from end of adjuvant ET or during first-line ET for mBC | Abemaciclib 150 mg/12 h continuously+fulvestrant versus fulvestrant alone | 16.4 versus 9.3 | 48 versus 21 | 72 versus 56 | - |
| Phase III placebo control | Postmenopausal, HR+/HER2−, ABC | 493 | 1st line | Abemaciclib 150 mg/12 h continuously+anastrozol or letrozole versus anastrozol or letrozole alone | 28.18 versus 14.76 | 61 versus 45.5 | 78 versus 71.5 | - |
Common side effects of cdk4/6 inhibitors.
| Palbociclib+letrozole | Neutropenia (80%), leukopenia (39%), fatigue (37%), nausea (35%), arthralgia (33%), alopecia (33%) | Neutropenia (66%), leukopenia (25%) |
| Palbociclib+fulvestrant | Neutropenia (81%), leukopenia (50%), infections (42%), fatigue (39%), nausea (32%) | Neutropenia (65%), leukopenia (28%) |
| Ribociclib+letrozole | Neutropenia (74%), nausea (52%), infections (50%), fatigue (37%), diarrhea (35%), alopecia (33%), leukopenia (39%) | Neutropenia (59%), leukopenia (21%) |
| Ribociclib+fulvestrant | Neutropenia (69.6%), nausea (45.3%), fatigue (31.5%) | Neutropenia (46.6%) (Grade 3) |
| Abemaciclib monotherapy | Leukopenia (91%), diarrhea (90%), neutropenia (88%), anemia (69%), fatigue (65%), nausea (64%), decreased appetite (46%), thrombocytopenia (41%), abdominal pain (39%), vomiting (35%) | Leukopenia (28%), neutropenia (27%), diarrhea (20%) |
| Abemaciclib+fulvestrant | Diarrhea (86%), neutropenia (46%), nausea (45%), fatigue (40%), abdominal pain (35%) | Neutropenia (23.6%) |
| Abemaciclib+NSAI | Diarrhea (81.3%), neutropenia (41.3%), fatigue (40.1%), infections and infestations (39.1%), nausea (38.5%) | Neutropenia (59%), leukopenia(21%) |