Metabolism
of Abemaciclib
Abemaciclib
is metabolized to several metabolites primarily by CYP3A.1
The
major metabolism pathway is formation of
Additional
metabolites include
hydroxyabemaciclib
(M20)
hydroxy-N-desethylabemaciclib
(M18), and
an
oxidative metabolite (M1).1
Of
these metabolites, M2, M18, and M20 are active with similar potency
as abemaciclib.1
Effect
of Other Drugs on Abemaciclib
Strong
CYP3A Inhibitors
Co-administration
of abemaciclib with CYP3A4 inhibitors can increase plasma
concentrations of abemaciclib. In patients with advanced and/or
metastatic cancer, co‑administration of the CYP3A4 inhibitor
clarithromycin resulted in a 3.4‑fold increase in the plasma
exposure of abemaciclib and a 2.5‑fold increase in the combined
unbound potency adjusted plasma exposure of abemaciclib and its
active metabolites.2
Use
of strong CYP3A4 inhibitors together with abemaciclib should be
avoided.2
Examples
of strong CYP3A4 inhibitors include, but not limited to:
clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir,
posaconazole or voriconazole. Avoid grapefruit or grapefruit juice. 2
Concomitant
use of strong CYP3A4 inhibitors should be avoided. If strong CYP3A4
inhibitors cannot be avoided, the abemaciclib dose should be reduced
to 100 mg twice daily.2
In
patients who have had their dose reduced to 100 mg abemaciclib
twice daily and in whom co-administration of a strong CYP3A4
inhibitor cannot be avoided, the abemaciclib dose should be further
reduced to 50 mg twice daily.2
In
patients who have had their dose reduced to 50 mg abemaciclib
twice daily and in whom co‑administration of a strong CYP3A4
inhibitor cannot be avoided, the abemaciclib dose may be continued
with close monitoring of signs of toxicity. 2
If
the CYP3A4 inhibitor is discontinued, the abemaciclib dose should be
increased to the dose used prior to the initiation of the CYP3A4
inhibitor (after 3 to 5 half-lives of the CYP3A4
inhibitor).2
Topical
ketoconazole is not expected to interact with abemaciclib due to
minimal systemic absorption of topical products.3
Avoid
grapefruit or grapefruit products.1
Moderate
CYP3A Inhibitors
No
dose adjustment is necessary for patients treated with moderate or
weak CYP3A4 inhibitors. There should, however, be close monitoring
for signs of toxicity.2
Strong
and moderate CYP3A Inducers
Co-administration
of abemaciclib with the strong CYP3A4 inducer rifampicin decreased
the plasma concentration of abemaciclib by 95% and unbound potency
adjusted plasma concentration of abemaciclib plus its active
metabolites by 77% based on AUC0-∞. 2
Concomitant
use of strong CYP3A4 inducers (including, but not limited to:
carbamazepine, phenytoin, rifampicin and St. John’s wort)
should be avoided due to the risk of decreased efficacy of
abemaciclib.2
Loperamide
Coadministration
of a single 8 mg dose of loperamide with a single 400 mg dose of
abemaciclib (2.7 times the approved recommended 150 mg dosage) in
healthy subjects increased the relative potency adjusted unbound
AUC0-INF of
abemaciclib plus its active metabolites by 12%, which is not
considered clinically relevant.1
Endocrine
Therapies
In
clinical studies in patients with breast cancer, there was no
clinically relevant effect of fulvestrant, anastrozole, letrozole, or
exemestane on the PK of abemaciclib.1
Acid-Reducing
Agents
Based
on the solubility and metal ion binding characteristics of
abemaciclib, acid-reducing agents are not expected to affect the oral
absorption of abemaciclib.1
A
clinical study to evaluate the impact of acid-reducing agents, such
as H2 blockers and proton pump inhibitors, on abemaciclib absorption
has not been conducted. However, because abemaciclib 200 mg is
soluble in solutions up to pH 6.8, coadministration of acid-reducing
agents is unlikely to have an effect on the absorption and exposure
of abemaciclib.1
An
in vitro study was conducted to evaluate the risk of an interaction
between abemaciclib and metal ions (magnesium, calcium, iron,
bismuth, zinc, and aluminum) commonly found in antacids. Abemaciclib
did not interact with any of the metal ions that are commonly found
in antacids.1
Effect
of Abemaciclib on Other Agents
Loperamide
In a
clinical drug interaction study in healthy subjects, coadministration
of a single 8 mg dose of loperamide with a single 400 mg dose of
abemaciclib in healthy subjects (2.7 times the approved recommended
150 mg dosage) increased the relative potency AUC0-INF
of abemaciclib plus its active metabolites by 12%, and increased
loperamide AUC0-INF
by 9% and Cmax
by 35% relative to loperamide alone. These effects are not considered
clinically relevant.1
Metformin
In a
clinical drug interaction study in healthy subjects, coadministration
of a single 1000 mg dose of metformin, a clinically relevant
substrate of renal OCT2, and MATE1 and 2-K transporters, with a
single 400 mg dose of abemaciclib (2.7 times the approved
recommended 150 mg dosage) increased metformin AUC0-INF
by 37% and Cmax
by 22% relative to metformin alone. Abemaciclib reduced the renal
clearance and renal secretion of metformin by 45% and 62%,
respectively, relative to metformin alone, without any effect on
glomerular filtration rate as measured by iohexol clearance and serum
cystatin C.1
Endocrine
Therapies
In a
clinical study in patients with breast cancer, there was no
clinically‑relevant pharmacokinetic drug interaction between
abemaciclib and anastrozole, fulvestrant, exemestane, letrozole or
tamoxifen.2
It
is currently unknown whether abemaciclib may reduce the effectiveness
of systemically acting hormonal contraceptives, and therefore women
using systemically acting hormonal contraceptives are advised to add
a barrier method.2
CYP
Metabolic Pathways
In a
phase 1 clinical drug interaction study, patients with advanced
and/or metastatic cancer received a drug cocktail containing 4
sensitive CYP substrates alone and in combination with abemaciclib.
The
drug cocktail CYP substrates included
0.2
mg midazolam (CYP3A4)
10
mg S-warfarin (CYP2C9)
30
mg dextromethorphan (CYP2D6), and
100
mg caffeine (CYP1A2).4
There
were no clinically meaningful changes in the PK of CYP1A2, CYP2C9,
CYP2D6, AND CYP3A4 substrates.1,4
The
following PK results were observed.
Midazolam
AUC0-inf
was approximately 13% lower and the Cmax
was approximately 15% lower when midazolam was administered in
combination with abemaciclib versus when midazolam was administered
alone,
no
significant differences in PK between S-warfarin and
dextromethorphan when administered in combination with abemaciclib,
and
AUC0-inf
of caffeine was 56% higher when caffeine was administered in
combination with abemaciclib compared to administration alone.4
Non-compliance
with caffeine restriction was evident in the data before and after
drug cocktail administration, but given the patient variability for
caffeine AUC, the effect observed for caffeine AUC0-INF
is not considered clinically relevant.4
In
Vitro Transporter Studies
Abemaciclib
and its major active metabolites inhibit the renal transporters OCT2,
MATE1, and MATE2-K at concentrations achievable at the approved
recommended dosage. The observed serum creatinine increase in
clinical studies with abemaciclib is likely due to inhibition of
tubular secretion of creatinine via OCT2, MATE1, and MATE2-K.
Abemaciclib and its major metabolites at clinically relevant
concentrations do not inhibit the hepatic uptake transporters OCT1,
OATP1B1, and OATP1B3, or the renal uptake transporters OAT1 and
OAT3.1
In
an in vitro study, abemaciclib and its major active metabolites
downregulated the mRNA of various CYP isoforms (1A2, 2B6, 2C8, 2C9,
2D6, 3A4, and 3A5) and decreased the catalytic activities of CYP1A2,
CYP2B6, and CYP3A4 enzymes. The results did not translate into
clinically meaningful drug-drug interactions. The lack of clinically
meaningful drug-drug interactions suggest further studies are needed
to understand the downregulation of CYP isoforms in vitro.4
Abemaciclib
is a substrate of P-gp and BCRP. Abemaciclib and its major active
metabolites are not substrates of hepatic uptake transporters OCT1,
OATP1B1, or OATP1B3.1
Abemaciclib
inhibits P-gp and BCRP. The clinical consequences of this finding on
sensitive P-gp and BCRP substrates are unknown.1
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.
3.
Lexicomp Online™ Lexi-Drugs: Ketoconazole (topical). In:
Lexi-Drugs, Lexicomp Online. Hudson, OH: Lexi-Comp, Inc. Available
at: http://online.lexi.com.
Updated August 10, 2018. Accessed September 10, 2018.
4.
Turner PK, Hall SD, Chapman SC, et al. Abemaciclib does not have a
clinically meaningful effect on pharmacokinetics of CYP1A2, CYP2C9,
CYP2D6, and CYP3A4 substrates in patients with cancer. Drug Metab
Dispos. 2020;48(9):796-803.
https://doi.org/10.1124/dmd.119.090092
Glossary
AUC
= area under the curve
AUC0-INF =
area under the curve from time zero to infinity
BCRP
= breast cancer resistance protein
Cmax
= maximum concentration
CYP
= cytochrome P450
MATE
= multidrug and toxin extrusion protein
mRNA
= messenger RNA
OAT
= organic anion transporter
OCT
= organic cation transporter
P-gp
= P-glycoprotein
PK =
pharmacokinetic(s)
▼ 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.