Treatment of palbociclib in hormone receptor positive breast cancer: a real-world study and efficacy prediction model / 中华肿瘤杂志

Objective: To summarize the clinical use of palbociclib and evaluate its efficacy and safety in hormone-receptor (HR)-positive advanced breast cancer patients. Methods: We retrospectively analyzed data from 66 HR-positive metastatic breast cancer patients treated with palbociclib and endocrine therapy at the Department of Oncology in the First Affiliated Hospital with Nanjing Medical University between 2018 and 2020. We evaluated the factors affecting the efficacy of palbociclib using Kaplan-Meier method and Log-rank test for survival analysis and Cox regressions for multivariate analysis. Nomogram model was built for predicting prognosis among HR-positive breast cancer patients who received palbociclib. Concordance index (C-index) and calibration curve were used for internal validation to assess the predictive ability and conformity of the model. Results: Of the 66 patients treated with palbociclib, 33.3%(22), 42.4%(28) and 24.2%(16) patients were treated without endocrine therapy, first-line endocrine therapy, second-line or above endocrine therapy after recurrence, respectively. 36.4%(24) patients had hepatic metastasis, 16.7% (11) patients were sensitive to previous endocrine therapy, 27.3%(18/66) patients had primary resistance to endocrine therapy, while 56.1% (37) patients had secondary resistance to endocrine therapy. The overall response rate was 14.3% (95% CI: 6.7%, 25.4%) and clinical benefit rate was 58.7% (95% CI: 45.6%, 71.0%). Better clinical outcomes were associated with non-hepatic metastasis (P=0.001), sensitive/secondary resistant to previous endocrine therapy (P=0.004), no or only one line of chemotherapy for metastatic breast cancer (P=0.004), recent pathological confirmation of immunohistochemical analysis (P=0.025). Hepatic metastasis (P=0.005) and primary resistance to endocrine therapy (P=0.016) were the independent risk factors of progression free survival. The C-index of predictive probability for the nomogram constructed from the patient clinical characteristics (whether liver metastasis, whether primary endocrine resistance, lines of chemotherapy after metastasis, lines of endocrine therapy, number of metastatic sites, and time to last immunohistochemistry) to predict the progression-free survival at 6 and 12 months for patients was 69.7% and 72.1%, respectively. The most common adverse events were hematologic toxicities. Conclusions: Our report indicates that palbociclib combined with endocrine therapy for HR-positive recurrent metastatic breast cancer is effective and safe; patients with hepatic metastases and primary resistance to endocrine therapy have worse prognoses and are independent risk factors for progression after palbociclib therapy. The constructed nomogram could help predict the survival and guide the use of palbociclib.

Study on the bioequivalence of Palbociclib capsules in human / 中国药房

OBJECTIVE To evaluate the bioequivalence of a single oral administration of two palbociclib preparations in healthy subjects under fasting and fed conditions. METHODS Twenty-four healthy subjects （fasting test） and twenty healthy subjects （fed test） were enrolled and divided into two groups. A single-center， open-label， single-dose， two-formulation， two- period， two-sequence and crossover trial was designed. The subjects in the two groups were given the test preparation （domestic Palbociclib capsules） or the reference preparation （original Palbociclib capsules） orally under fasting or fed conditions respectively followed by a 14-day washout period. The blood samples were collected at different time points before and after treatment. After pretreatment， the mass concentration of palbociclib in vivo was determined by high-performance liquid chromatography-tandem mass spectrometry with palbociclib-d8 as the internal standard. SAS V9.4 software was used to calculate the pharmacokinetic parameters and evaluate the bioequivalence. RESULTS Under fasting condition， the cmax of the test preparation and the reference preparation were （71.4±18.1） and （73.8±19.0） ng/mL； AUC0－t were （1 754±412） and （1 793±448） h·ng/mL； AUC0－∞ were （1 851±456） and （1 887±478） h·ng/mL， respectively. Under fed condition， the cmax of the test preparation and the reference preparation were （78.4±18.3） and （81.9±21.7） ng/mL； AUC0－t were （1 905±375） and （1 932±318） h·ng/mL； AUC0－∞ were （2 027±411） and （2 050±342） h·ng/mL， respectively. The 90%CI of the geometric mean ratio of the above parameters was within the acceptable range （80.00%-125.00%）. Under fasting and fed conditions， there were 20 and 16 adverse events in 9 and 8 subjects， respectively， but no serious adverse event was observed. CONCLUSIONS Under the fasting and fed conditions， the test preparation and the reference preparation of Pibociclib capsules are bioequivalent and have comparable safety.

Recent Progress of Palbociclib in Treatment of HR+/HER2- Breast Cancer / 肿瘤防治研究

As the first cyclin-dependent kinases 4 and 6 inhibitors, palbociclib significantly improved the survival of the patients with the hormone receptor-positive and human epidermal growth factor receptor-2 negative breast cancer. Palbociclib is a crucial landmark in the development history of antineoplastic drugs. This article reviews the mechanism of palbociclib, and summarizes the clinical trials, side effects, and the application of palbociclib.

Acute Lymphoblastic Leukemia in a Patient Treated with Letrozole and Palbociclib / 한국유방암학회지

Palbociclib, in conjunction with endocrine therapy, has been approved for the treatment of patients with advanced breast cancer. The common hematological toxicities associated with palbociclib are leukopenia and neutropenia. However, hematological malignancies have not been reported for palbociclib treatment. Here, for the first time, we present a case of acute lymphoblastic leukemia that was diagnosed in a patient undergoing treatment with letrozole and palbociclib for metastatic breast cancer. This case emphasizes the need for long term follow up of patients treated with palbociclib.

Palbociclib induces cell cycle arrest and senescence of human renal tubular epithelial cells / 南方医科大学学报

OBJECTIVE@#To investigate the effect of palbociclib on cell cycle progression and proliferation of human renal tubular epithelial cells.@*METHODS@#Human renal tubular epithelial cell line HK-2 was treated with 1, 5, 10, and 20 μmol/L of palbociclib, and the changes in cell proliferation and viability were examined by cell counting and CCK8 assay. EDU staining was used to assess the proliferation of HK-2 cells following palbiciclib treatment at different concentrations for 5 days. The effect of palbociclib on cell cycle distribution of HK-2 cells was evaluated using flow cytometry. SA-β-Gal staining and C12FDG senescence staining were used to detect senescence phenotypes of HK-2 cells after palbociclib treatment at different concentrations for 5 days. The relative mRNA expression levels of P16, P21, and P53 and the genes associated with senescence-related secretion phenotypes were detected by RT-PCR, and the protein expressions of P16, P21 and P53 were detected by Western blotting.@*RESULTS@#Palbociclib inhibited HK-2 cell proliferation and induced cell cycle arrest in G1 phase. Compared with the control cells, HK-2 cells treated with high-dose (10 μmol/L) palbociclib exhibited significantly suppressed cell proliferation activity, and the inhibitory effect was the most obvious on day 5 (@*CONCLUSIONS@#Palbociclib induces HK-2 cell senescence by causing cell growth arrest and delaying cell cycle progression.

Qualitative and quantitative analysis of palbociclib / 药学学报

In this paper, three methods, differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and X-ray powder diffraction (PXRD), were used to characterize the structure of Palbociclib. The form-B crystal mixed in with form-A crystal, the effective form of Palbociclib, was quantitated by the single peak method (peak area method and peak height method) using X-ray powder diffraction. While the qualitative identification by DSC was not clear, SEM and PXRD quickly and effectively identified two types of crystal. The standard curve equations established by the peak area method and the peak height method are: y = 0.842 75x - 0.001 21 and y = 0.909 64x - 0.002 32. This suggests that the linear relationship of peak area method is better than that of peak height method (R2 = 0.986 17 and R2 = 0.985 83). The sensitivity of the peak area method (LOD = 1.17%, LOQ = 3.92%) are higher than the peak height method (LOD = 1.19%, LOQ = 3.97%). The methods from this study can be used to identify and quantify palbociclib form-A and form-B crystal rapidly.

Experiencia institucional con Palbociclib. Estudio Prospectivo / Institutional experience with Palbociclib. Prospective Study

La ANMAT aprobó en diciembre de 2015 el uso de palbociclib en combinación con letrozol para el tratamiento de primera línea del cáncer de mama metastásico con receptores hormonales positivos y HER2 negativo, y en agosto de 2016 la combinación de palbociclib con fulvestrant para pacientes progresadas a terapia endocrina previa. El propósito del presente estudio fue realizar una evaluación prospectiva de la seguridad y eficacia del tratamiento con palbociclib en el Instituto de Oncología Ángel Roffo. Se evaluaron en forma prospectiva 71 pacientes con cáncer de mama metastásico que calificaron para tratamiento con palbociclib desde marzo de 2016 hasta junio de 2017 inclusive. Las participantes fueron tratadas con palbociclib/letrozol (n = 49) o palbociclib/fulvestrant (n = 22). La mediana de tratamiento con palbociclib/ letrozol fue de 5 meses; 3 pacientes presentaron progresión de la enfermedad, y 36 se encuentran en respuesta parcial. La mediana de tratamiento con palbociclib/fulvestrant fue de 2.6 meses; 3 experimentaron progresión de la enfermedad, mientras que el resto de las participantes de este grupo se encuentran con respuesta parcial. En total, 26 tratadas con palbociclib presentaron toxicidades hematológicas, destacándose la neutropenia de grados I a III, anemia de grados I a II, y plaquetopenia grado III. No se registraron toxicidades de grado IV. A pesar del breve período de seguimiento (16 meses), nuestras pacientes evolucionaron con escasa cantidad de progresiones (8.4%), de acuerdo con lo descrito en la literatura, y con menor toxicidad que la comunicada (36.7%) (AU)

In December 2015, ANMAT approved the use of palbociclib in combination with letrozole for the first-line treatment of hormone-receptor-positive and HER2-negative metastatic breast cancer. Subsequently, the combination of palbociclib with fulvestrant was approved in August 2016 for patients progressing from previous endocrine therapy. The purpose of the present study was to conduct a prospective evaluation of safety and efficacy of palbociclib treatment at Instituto de Oncología Ángel H. Roffo. Seventy one patients with metastatic breast cancer who qualified for treatment with palbociclib from March 2016 to June 2017, were evaluated prospectively. Participants were treated with palbociclib/letrozole (n = 49) or palbociclib/ fulvestrant (n = 22). Median of treatment with palbociclib/letrozole was 5 months; 3 patients showed progression of the disease, and 36 are in partial response. Median of treatment with palbociclib/fulvestrant was 2.6 months; 3 patients experienced disease progression, while the rest of the participants in this group were in partial response. In total, 26 treated with palbociclib presented haematological toxicities, including neutropenia grades I to III, anaemia in grades I to II, and thrombocytopenia grade III. No grade IV toxicities were recorded. Despite the brief follow-up period (16 months), our patients experienced a low number of progression (8.4%), as described in the literature, and with less toxicity than reported (36.7%) (AU)

Reversal effect of palbociclib on the resistance of breast cancer MCF-7 cells to doxorubicin / 肿瘤

Objective: To study the reversal effect of cyclin-dependent protein kinase 4/6 (CDK4/6) inhibitor palbociclib (PAL) on the resistance of breast cancer MCF-7/doxorubicin (DOX) cells to DOX, and to explore its mechanism from the view of drug efflux transporter ATP binding cassette protein B1 (ABCB1). Methods: The effect of PAL on the sensitivity of parental MCF-7 and resistant MCF-7/DOX cells to DOX was detected by CCK-8 method. The effect of PAL on intracellular accumulation of DOX in MCF-7 and MCF-7/DOX cells was determined by FCM analysis. The MDCK II cell model stably transfected with ABCB1 gene was constructed, then the effect of PAL on the ABCB1-mediated efflux function of DOX was detected by drug transmembrane bi-direction transport assay. The effect of PAL on the expressions of ABCB1 mRNA and protein in MCF-7 and MCF-7/DOX cells was detected by real-time fluorescent quantitative PCR and Western blotting, respectively. Results: After treatment with 0.2 and 0.4 μmol/L PAL, the half maximal inhibitory concentration (IC50) values of DOX in MCF-7/DOX cells were decreased by 39% and 51%, respectively (both P < 0.05), but the IC50 value of DOX in MCF-7 cells had no obvious change. In MCF-7/DOX cells treated with 0.4 μmol/L PAL, the intracellular accumulation of DOX was increased by 82% (P < 0.05), but the concentration of DOX in MCF-7 cells did not change. PAL significantly inhibited the ABCB1 -mediated efflux of DOX, but had no obvious regulatory effect on the expressions of ABCB1 mRNA and protein in MCF-7 cells and MCF-7/DOX cells. Conclusion: PAL can reverse DOX-resistance of breast cancer cells by inhibiting the function of drug transporter ABCB1, which suggests that coadministration of PAL and DOX maybe improve the effiocacy of DOX in breast cancer and optimize the clinical treatment.

Analysis and synthesis of the related substances of palbociclib / 中国药科大学学报

@#To strengthen the quality control of palbociclib, three related substances were separated from the bulk drug. These substances were identified as 8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido ［2, 3-d］ pyrimidin-7(8H)-one(A), 8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridine-2-yl)amino)-6-vinylpyrido ［2, 3-d］ pyrimidin-7(8H)-one(B), tert-butyl4-(6-((6-acetyl-8-cyclopentyl-5-methyl-7-oxo-7, 8-dihydropyrido ［2, 3-d］ pyrimidin-2-yl)amino)pyridin-3-yl)piperazi-ne-1-carboxylate(C). Based on the structures of the impurities, the possible routes to them were discussed, and their structures were elucidated by 1H NMR and MS.