Avoid concomitant use of the strong CYP3A inhibitor ketoconazole.1

With concomitant use of strong CYP3A inhibitors other than ketoconazole, in patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the abemaciclib dose to 100 mg twice daily. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the abemaciclib dose to 50 mg twice daily.1

If a patient taking abemaciclib discontinues a CYP3A inhibitor, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.1

Strong and moderate CYP3A4 inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity.1 Strong CYP3A inhibitors include:

• Ketoconazole: Predicted to increase the area under the curve (AUC) of abemaciclib by up to 16-fold.1
• Clarithromycin: Coadministration of clarithromycin 500 mg twice daily with a single 50 mg dose of abemaciclib (0.3 times the approved recommended 150 mg dosage), increased the relative potency adjusted unbound area under the curve from time zero to infinity (AUC_0-INF) of abemaciclib plus its active metabolites by 2.5-fold relative to abemaciclib alone in cancer patients.1
• Lopinavir/ritonavir: Coadministration of lopinavir/ritonavir 50 mg increased the relative potency-adjusted unbound AUC of abemaciclib plus its active metabolites by 2.5-fold.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

Grapefruit and its juice contain furanocoumarins, such as bergamottin, epoxybergamottin, and 6′,7′-dihydroxybergamottin, that inhibit the CYP3A4 enzyme.4 

Other citrus fruits like Seville oranges, pomelos, and limes may also contain relatively high levels of furanocoumarins.5-7

Lilly has not systematically evaluated the pharmacokinetic interactions of abemaciclib with citrus fruits.

With concomitant use with moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the abemaciclib dose in 50 mg decrements if necessary.1

• Verapamil and diltiazem: Predicted to increase the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 1.6-fold and 2.4-fold, respectively.1

Coadministration of CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity. Avoid concomitant use of CYP3A inducers and consider alternative agents.1

• Rifampin (strong CYP3A inducer): Coadministration of 600 mg daily doses of rifampin with a single 200 mg dose of abemaciclib decreased the relative potency adjusted unbound AUC_0-INF of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.1
• Efavirenz, bosentan, and modafinil (moderate CYP3A inducers): Predicted to decrease the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 53%, 41%, and 29%, respectively.1

Coadministration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib 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

In clinical studies in patients with breast cancer, there was no clinically relevant effect of fulvestrant, anastrozole, letrozole, exemestane or tamoxifen on the pharmacokinetics (PK) of abemaciclib.1

Based on the solubility and metal ion binding characteristics of abemaciclib, acid-reducing agents are not expected to affect the oral absorption of abemaciclib.8

A clinical study to evaluate the impact of acid-reducing agents, such as histamine H2-receptor antagonists (H2) blockers and proton pump inhibitors, on abemaciclib absorption has not been conducted. However, because abemaciclib 200 mg is soluble in solutions up to potential of hydrogen (pH) 6.8, coadministration of acid-reducing agents is unlikely to have an effect on the absorption and exposure of abemaciclib.8

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.8

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 maximum concentration (C_max) by 35% relative to loperamide alone. These effects are not considered clinically relevant.1

In a clinical drug interaction study in healthy subjects, coadministration of a single 1000 mg dose of metformin, a clinically relevant substrate of renal organic cation transporter (OCT) 2, and multidrug and toxin extrusion protein (MATE) 1 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

In clinical studies in patients with breast cancer, there was no clinically relevant effect of abemaciclib on the PK of fulvestrant, anastrozole, letrozole, exemestane or tamoxifen.1

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).9

There were no clinically meaningful changes in the PK of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 substrates.9

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.9

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.9

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, organic anion transporter (OAT) P1B1, and OATP1B3, or the renal uptake transporters OAT1 and OAT3.1

In an in vitro study, abemaciclib and its major active metabolites downregulated the messenger RNA (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.9 

Abemaciclib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (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