Verzenios® ▼ (abemaciclib): Drug Interactions

Metabolism of Abemaciclib

Abemaciclib is metabolized to several metabolites primarily by CYP3A.¹

The major metabolism pathway is formation of

• N-desethylabemaciclib (M2).¹

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 AUC_0-∞. 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 AUC_0-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 AUC_0-INF of abemaciclib plus its active metabolites by 12%, and increased loperamide AUC_0-INF by 9% and C_max 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 AUC_0-INF by 37% and C_max 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 AUC_0-inf was approximately 13% lower and the C_max 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 

• AUC_0-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 AUC_0-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

AUC_0-INF = area under the curve from time zero to infinity

BCRP = breast cancer resistance protein

C_max = 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.