Verzenios ® (abemaciklib)

För fullständig produktresumé för Verzenios se FASS.

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Verzenios® ▼ (abemaciclib): Läkemedelsinteraktioner

Abemaciclib kan interagera med cytokrom P450 (CYP) 3A4-läkemedel och kan orsaka interaktion med substrat av OCT2, MATE1 eller 2-K eller kritiska substrat av P-gp- eller BCRP-transportörer.

Metabolism of Abemaciclib

Hepatic metabolism is the main route of clearance for abemaciclib. Abemaciclib is metabolised to several metabolites primarily by cytochrome P450 (CYP) 3A4. The primary biotransformation is hydroxylation to a metabolite that circulates with an AUC that is 77% of parent drug. In addition, N-desethyl and N-desethylhydroxy metabolites circulate at AUCs that are 39% and 15% of parent drug. These circulating metabolites are active with similar potency to 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.1

Use of strong CYP3A4 inhibitors together with abemaciclib should be avoided.1

Examples of strong CYP3A4 inhibitors include, but not limited to: clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole or voriconazole. Avoid grapefruit or grapefruit juice. 1

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.1

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.1

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. 1


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).1

Topical ketoconazole is not expected to interact with abemaciclib due to minimal systemic absorption of topical products.2

Avoid grapefruit or grapefruit products.3

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.1

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-∞1

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.1

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.3

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.3

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.3

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.3

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.3

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.3

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.3

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.1

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.1

In Vitro Transporter Studies

Abemaciclib and its major active metabolites inhibit the renal transporters organic cation transporter 2 (OCT2), multidrug and extrusion toxin protein (MATE1), and MATE2‑K. In vivo interactions of abemaciclib with clinically relevant substrates of these transporters, such as dofetilide or creatinine, may occur.1

In a clinical drug interaction study with metformin (substrate of OCT2, MATE1 and 2) co-administered with 400 mg abemaciclib, a small but not clinically relevant increase (37%) in metformin plasma exposure was observed. This was found to be due to reduced renal secretion with unaffected glomerular filtration.1

Abemaciclib inhibits P-gp and BCRP.3

In healthy subjects, co-administration of abemaciclib and the P‑glycoprotein (P-gp) substrate loperamide resulted in an increase in loperamide plasma exposure of 9% based on AUC0-∞ and 35% based on Cmax. This was not considered to be clinically relevant. However, based on the in vitro inhibition of P-gp and breast cancer resistance protein (BCRP) observed with abemaciclib, in vivo interactions of abemaciclib with narrow therapeutic index substrates of these transporters, such as digoxin or dabigatran etexilate, may occur.1

Abemaciclib and its major metabolites at clinically relevant concentrations do not inhibit the hepatic uptake transporters OCT1, organic anion transporting polypeptide (OATP) 1B1 (OATP1B1) and OATP1B3, or the renal uptake transporters OAT1 and OAT3.3

Abemaciclib and its major active metabolites do not induce CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations. Abemaciclib and its major active metabolites down regulate mRNA of CYPs, including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. The mechanism of this down regulation and its clinical relevance are not understood. However, abemaciclib is a substrate of CYP3A, and time-dependent changes in PK of abemaciclib as a result of autoinhibition of its metabolism was not observed.3

References

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

2. 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.

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

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.

Datum fӧr senaste ӧversyn 2019 M03 22

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