Dose adjustment is not necessary in patients with mild or moderate renal impairment (creatinine clearance [CrCL] ≥30-89 mL/min, estimated by Cockcroft-Gault [CG]).1

In a population pharmacokinetic analysis, mild and moderate renal impairment did not affect the exposure of abemaciclib.1

The population pharmacokinetic analysis evaluated 989 individuals including

• 383 individuals with mild renal impairment (60 mL/min ≤ CrCL <90 mL/min), and
• 127 individuals with moderate renal impairment (30 mL/min ≤ CrCL <60 mL/min).1

While abemaciclib is not contraindicated, we have no data in patients

• with severe renal impairment (creatinine clearance estimated by Cockroft-Gault <30 mL/min)
• with end stage renal disease, or
• on dialysis.1,2

Administer abemaciclib with caution in patients with severe renal impairment and closely monitor for signs of toxicity.2

Two case studies are available that discuss the use of abemaciclib in patients on dialysis Case studies of two patients with end-stage renal disease and on dialysis 

Studies indicated that hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 3A.1

The geometric mean hepatic clearance of abemaciclib was 21.8 L/h (39.8% coefficient of variation [CV]), and the mean plasma elimination half-life for abemaciclib in patients was 24.8 hours (52.1% CV). After a single oral dose of radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3.4% recovered in urine. The majority of the dose eliminated in feces was metabolites.1

Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters without affecting glomerular function.1,3

In the MONARCH 1, MONARCH 2, and MONARCH 3 trials, increased serum creatinine was the most common laboratory abnormality reported, with 98%, 97%, and 96% of patients, respectively, having a grade 1 or 2 event.4-6

In healthy subjects, mean maximum creatinine increases of approximately 20% to 35% over baseline values occurred at about 24 hours post-dose and then returned to baseline at about 336 hours (14 days) post-dose.1

In clinical studies, increases in serum creatinine (mean increase 0.2-0.3 mg/dL)

• occurred within the first 28-day cycle of abemaciclib dosing
• remained elevated but stable throughout the treatment period, and
• were reversible upon treatment discontinuation.1,7,8

The incidence of dose reduction, omission, and discontinuation due to elevated creatinine was <2.5% across both MONARCH 2 and MONARCH 3 studies and only occurred in the abemaciclib arms. Dose reductions, omissions and discontinuations in MONARCH 2 and MONARCH 3 due to increased creatinine shows the detailed breakdown from the studies.7

Other measures of renal function (such as blood urea nitrogen, cystatin C, or calculated glomerular filtration rate based on cystatin C) should be used as an alternative to either serum creatinine or creatinine-based calculated estimates of glomerular filtration rate (GFR) if

• serum creatinine rise is progressive after the first cycle
• there are other indications of renal injury (eg, proteinuria, etc.), or
• a patient has a need for precise GFR assessment (such as concomitant medications that effect kidney function).7,9,10

Creatinine may not be an accurate method to assess renal function in these patients.7,9-11

Cystatin C is a small protein that is produced by all nucleated cells and found in body fluids, including serum. It is formed at a constant rate and due to its small size is freely filtered by the glomeruli. Cystatin C is not secreted and is fully reabsorbed and broken down by the renal tubules.12 Cystatin C has been consistently found to have a higher correlation with standard measures of GFR when compared with creatinine.13

Serum or plasma cystatin C measurement is an automated test that is readily available and does not require special processing or handling of the blood sample.14

The case studies discuss the treatment of two patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and end-stage renal disease (ESRD) who were undergoing haemodialysis. Both patients received standard hormonal therapy plus abemaciclib 100 mg twice daily under strict monitoring for toxicity.15 

Patient 1. The first patient was a 68-year-old woman who had been on adjuvant letrozole for 3 years before experiencing disease progression. She received fulvestrant and abemaciclib, and despite experiencing grade 2 diarrhoea initially (after 10 days), the side effect was managed with dietary changes and loperamide. The patient showed a partial response to the treatment after 12 months, and was at the time of publication of the case report still under the same treatment with no sign of progressive disease.15

Patient 2. A 47-year-old woman who had previously undergone surgery and received adjuvant LHRH and tamoxifen for 5 years. She developed metastatic disease and was treated with letrozole and abemaciclib. The patient tolerated the treatment well, with only mild grade 1 neutropenia and anaemia, recorded after 4 months of treatment without need of dose modification. No further safety signals, e.g. thrombocytopenia, deep venous thrombosis or interstitial lung disease were observed. At time of publication and after 9 months of treatment, the patient presented with stable disease.15

Throughout the treatment, both patients were closely monitored for toxicity, renal function, and other potential adverse effects. Renal function, as measured by creatinine and blood urea nitrogen (BUN) levels, remained relatively stable during the treatment period.15

Measurements of creatinine clearance of both patients throughout the treatment with abemaciclib are shown in Creatinine clearance throughout the treatment period with abemaciclib

The case studies highlight the importance of joint decision-making, expectation setting and appropriate counselling when treating patients with metastatic breast cancer and end-stage renal disease. Limited data are available in the medical literature regarding the use of cyclin-dependent kinase inhibitors (CDKIs) in this patient population. In these two cases, abemaciclib in combination with antihormonal therapy showed good response and safety. Mild diarrhoea and asthenia were the most common adverse events observed.15