Serum concentration of the CKD4/6 inhibitor abemaciclib, but not of creatinine, strongly predicts hematological adverse events in patients with breast cancer: a preliminary report

• Published in: Investigational new drugs Vol. 39; no. 1; pp. 272 - 277
• Main Authors: Maeda, Akimitsu, Irie, Kei, Hashimoto, Naoya, Fukushima, Shoji, Ando, Hitoshi, Okada, Akira, Ebi, Hiromichi, Kajita, Masaki, Iwata, Hiroji, Sawaki, Masataka
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2021; Springer Nature B.V
• Subjects: Adult; Aged; Aminopyridines - adverse effects; Aminopyridines - therapeutic use; Anemia; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Benzimidazoles - adverse effects; Benzimidazoles - therapeutic use; Breast cancer; Breast Neoplasms - drug therapy; Creatinine; Creatinine - blood; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Extrusion; Female; Hematologic Diseases - chemically induced; Hematology; Humans; Inhibitors; Leukocytes (neutrophilic); Male; Medicine; Medicine & Public Health; Middle Aged; Neutropenia; Neutrophils - metabolism; Oncology; Organic cation transporter; Patient Acuity; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Platelet Count; Short Report; Steady state; Thrombocytopenia; Toxicity; Creatinine; Adverse event; Abemaciclib; Pharmacokinetics
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-020-00994-3

Summary Purpose The CKD4/6 inhibitor abemaciclib is related to adverse events such as hematological toxicity and increase in serum creatinine levels associated with abemaciclib pharmacokinetics. Increase in serum creatinine levels is considered a result of competition with abemaciclib via organic cation transporter 2 and multidrug and toxic compound extrusion. Therefore, we evaluated the association among serum creatinine levels, serum abemaciclib concentrations, and adverse events and whether increase in serum creatinine levels is a useful indicator for predicting the onset of the adverse events of abemaciclib.  Methods In total, the data of 12 patients with breast cancer who were treated with abemaciclib (150 mg twice daily) were evaluated to determine the association between increased serum creatinine levels and abemaciclib concentrations and hematological toxicity.  Results Grade 3 neutropenia, thrombocytopenia, and anemia were observed at 4 weeks in four (33%), two (17%), and one (8%) patients, respectively. A significant association was observed between steady-state abemaciclib concentrations and the rate of decrease in neutrophil and platelet counts (r = − 0.80, P = 0.003 and r = − 0.70, P = 0.016, respectively). Compared with baseline levels (0.61 [0.53–0.82] mg/mL), serum creatinine levels significantly increased and reached a steady state in at least 2 weeks (0.84 [0.61–1.02] mg/mL, P = 0.01). However, we did not find a significant association between increase in serum creatinine levels and abemaciclib concentrations and hematological toxicity.  Conclusions Abemaciclib concentrations are associated with neutropenia and thrombocytopenia. However, increase in serum creatinine levels may not be a useful predictor for estimating abemaciclib pharmacokinetics and hematological toxicity.