Verzenios ® (abemaciklib)

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Verzenios® ▼ (abemaciclib): Levermetabolism

Abemaciclib metaboliseras i levern. Hämning av CYP 3A4 metabolism, ökning av ALAT och/ eller ASAT, eller leverinsufficiens kan kräva dosjustering.

Metabolism and Elimination

Studies indicated that hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolized to several metabolites primarily by CYP3A.1

The geometric mean hepatic clearance of abemaciclib was 22 L/h (40% CV), and the mean plasma elimination t1/2 for abemaciclib in patients was 25 hours (52% CV). After a single oral dose of 150 mg radiolabeled abemaciclib, approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.1

Hepatotoxicity

Liver function abnormalities are presented in Table 1.

Grade ≥3 increases in ALT and AST were reported in patients receiving abemaciclib in breast cancer studies. Based on the level of ALT and AST elevations, abemaciclib may require dose modification as shown in Table 1.2 Generally, the increases in hepatic transaminases were manageable by dose reduction or dose suspension and resolved upon discontinuation of study treatment.1

Table 1. ALT and AST Increases in MONARCH 2 and MONARCH 31


Abemaciclib + NSAI
N=327

Placebo + NSAI
N=161

Abemaciclib + Fulvestrant
N=441

Placebo + Fulvestrant
N=223

Event

MONARCH 3 

MONARCH 2

Grade ≥3 ALT increase

6%

2%

4%

2%

Median time to onset

64 days

---

57 days

---

Median time to resolutiona

14 days

---

14 days

---

Grade ≥3 AST increase

4%

1%

2%

3%

Median time to onset

87 days

---

185 days

---

Median time to resolutiona

15 days

---

13 days

---

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; NSAI = nonsteroidal aromatase inhibitor.

a To normalization or grade <3.

Blood Bilirubin Increased

Increases in blood bilirubin were reported in patients receiving abemaciclib in breast cancer studies and are presented in Table 2, Table 3, and Table 4.

Table 2. Blood Bilirubin Increased in MONARCH 11

 

CTCAE, %

All Grades

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Abemaciclib N=132

Blood bilirubin increased

2.3

0.8

1.5

0

0

0

Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.

Table 3. Blood Bilirubin Increased in MONARCH 21

CTCAE, %

All Grades

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

Abemaciclib + Fulvestrant, N=441

Blood bilirubin increased

1.6

0

0.7

0.9

0

0

 

Placebo + Fulvestrant, N=223

Blood bilirubin increased

0.9

0.4

0.4

0

0

0

Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.

Table 4. Blood Bilirubin Increased in MONARCH 31

CTCAE, %

All Grades

Grade 1

Grade 2

Grade 3

Grade 4

Grade 5

 

Abemaciclib + NSAI, N=327

Blood bilirubin increased

1.8

0.6

0.3

0.9

0

0

 

Placebo + NSAI, N=161

Blood bilirubin increased

0.6

0.6

0

0

0

0

Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; NSAI = nonsteroidal aromatase inhibitor.

Dose Modifications

Hepatic Impairment

Following a single 200 mg oral dose of abemaciclib, the relative potency adjusted unbound AUC0-INF of abemaciclib plus its active metabolites (M2, M18, M20) in plasma increased

  • 1.2-fold in subjects with mild hepatic impairment (Child-Pugh A, n=9)

  • 1.1-fold in subjects with moderate hepatic impairment (Child-Pugh B, n=10), and

  • 2.69-fold in subjects with severe hepatic impairment (Child-Pugh C, n=6) relative to subjects with normal hepatic function (n=10).1

In subjects with severe hepatic impairment, the abemaciclib t1/2 increased to 55 hours compared to 24 hours in subjects with normal hepatic function.1

For patients with severe hepatic impairment (Child-Pugh C), decrease the abemaciclib dosing frequency to once daily. No dosage adjustments are necessary in patients with mild or moderate hepatic impairment (Child-Pugh A or B).1

Hepatic Toxicity

Monitor ALT, AST, and serum bilirubin

  • prior to the start of abemaciclib therapy

  • every 2 weeks for the first 2 months

  • monthly for the next 2 months, and

  • as clinically indicated.1

Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent grade 2, or grade 3 or 4, hepatic transaminase elevation as shown in Table 5.1

Table 5. Abemaciclib Dose Modification and Management — Hepatotoxicity1

CTCAE Grade

Abemaciclib Dose Modifications

Grade 1 (>ULN-3.0 x ULN)
Grade 2 (>3.0-5.0 x ULN)

No dose modification is required.

Persistent or recurrent Grade 2, or Grade 3 (>5.0-20.0 x ULN)

Suspend dose until toxicity resolves to baseline or grade 1.
Resume at next lower dose.

Grade 3 (˃5.0 x ULN) with total bilirubin >2 x ULN, in the absence of cholestasis

Discontinue abemaciclib.

Grade 4 (>20.0 x ULN)

Discontinue abemaciclib.

Abbreviations: ALT = alanine transaminase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events; ULN = upper limits of normal.

References

1. Data on file, Eli Lilly and Company and/or one of its subsidiaries.

2. Verzenios [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Glossary

ALT = alanine transaminase

AST = aspartate aminotransferase

AUC0-∞ = area under the curve from time zero to infinity

CV = coefficient of variation

CYP = cytochrome P450

t1/2 = half-life

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

Datum fӧr senaste ӧversyn 2019 M10 23


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