Abemaciclib is metabolized to several metabolites primarily by cytochrome P450 (CYP) 3A in the liver.1

The main metabolite is

• 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

Yes. Co-administration of abemaciclib with CYP3A4 inhibitors can increase plasma concentrations of abemaciclib. In patients with advanced 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

Examples of strong CYP3A4 inhibitors include, but not limited to:

• clarithromycin
• itraconazole
• ketoconazole (except for topical ketoconazole, because of minimal systemic absorption of topical products)3  
• lopinavir/ritonavir
• posaconazole or
• voriconazole2

Avoid the concomitant use of strong CYP3A4 inhibitors, as well as grapefruit, grapefruit juice or other grapefruit products.2

Yes, however, no dose adjustment is necessary for patients treated with moderate or weak CYP3A4 inhibitors. Closely monitor patients for signs of toxicity.2

Yes. 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

Examples of strong CYP3A4 inducers include, but are not limited to

• carbamazepine
• phenytoin
• rifampicin, or
• St. John’s wort.

Avoid concomitant use of strong CYP3A4 inducers.2

The interaction between loperamide and abemaciclib is not considered clinically relevant. Coadministration of a single 8 mg dose of loperamide with a single 400 mg dose of abemaciclib in healthy people increased the relative potency adjusted unbound AUC_0-INF of abemaciclib plus its active metabolites by 12%.1

A clinical study in patients with breast cancer found no clinically‑relevant pharmacokinetic drug interaction between abemaciclib and anastrozole, fulvestrant, exemestane, letrozole or tamoxifen.1,2

We don’t know if abemaciclib reduces the effectiveness of hormonal contraceptives, and therefore women should add a barrier method for contraception.2

Abemaciclib did not interact with any of the metal ions that are commonly found in antacids, based on an in-vitro study that evaluated the interaction between abemaciclib and metal ions (magnesium, calcium, iron, bismuth, zinc, and aluminum) commonly found in antacids.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.1

We did not study the interaction between abemaciclib and acid reducing agents, such as histamine H2-receptor agonists blockers or proton pump inhibitors. 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

Co-administration of a single 1000 mg dose of metformin with a single 400 mg dose of abemaciclib

• increased metformin AUC_0-INF by 37%
• increased metformin C_max by 22%
• reduced the renal clearance of metformin by 45%, and
• reduced the renal secretion of metformin by 62%.

The interaction had no effect on the glomerular filtration rate, as measured by by iohexol clearance and serum cystatin C.1

There were no clinically meaningful changes in the pharmacokinetic (PK) of CYP1A2, CYP2C9, CYP2D6, or CYP3A4 substrates and abemaciclib, based on a phase 1 clinical drug interaction study. Patients with advanced or metastatic cancer received a drug cocktail containing 4 sensitive CYP substrates alone and in combination with abemaciclib.1,4

The drug cocktail included

• 0.2 mg midazolam (CYP3A4)
• 10 mg S-warfarin (CYP2C9)
• 30 mg dextromethorphan (CYP2D6), and
• 100 mg caffeine (CYP1A2).4
  

The authors 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 relevant4

Abemaciclib is a substrate and inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). The clinical consequences of this finding on sensitive P-gp and BCRP substrates are unknown.1

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.4

Abemaciclib and its major active metabolites are not substrates of hepatic uptake transporters OCT1, OATP1B1, or OATP1B3.1