sábado, 30 de septiembre de 2017

Clinical Pharmacology Corner: FDA Approves VERZENIO (Abemaciclib) for Treatment of Certain Advanced or Metastatic Breast Cancers

FDA Approves VERZENIO (Abemaciclib) for Treatment of Certain Advanced or Metastatic Breast Cancers

On September 28, 2017, the U.S. Food and Drug Administration (FDA) approved VERZENIO (abemaciclib) as follows:
  • In combination with fulvestrant for treatment of women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy. The approved recommended dose of VERZENIO in combination with fulvestrant is 150 mg taken orally twice daily. When given with VERZENIO, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, and 29; and once monthly thereafter. Refer to the full prescribing information for fulvestrant linked below.  Pre/perimenopausal women treated with the combination of VERZENIO plus fulvestrant should be treated with a gonadotropin-releasing hormone agonist according to current clinical practice standards.
  • As monotherapy for treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting. The recommended dose of VERZENIO as monotherapy is 200 mg taken orally twice daily.  
Continue treatment until disease progression or unacceptable toxicity. For recommended VERZENIO dose modifications and management for adverse reactions, refer to the applicable full prescribing information linked below.

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 
  • MOA: VERZENIO is a cyclin-dependent kinase inhibitor.
  • General PK: Following single and repeated dosing, the increase in AUC and Cmax was dose proportional. The estimated geometric mean accumulation ratio was 2.3 (50% CV) and 3.2 (59% CV) based on Cmax and AUC, respectively.
  • Absorption: The absolute bioavailability after a single dosing is 45% (19% CV). The median Tmax of abemaciclib is 8.0 hours (range: 4.1-24.0 hours).
  • Distribution [mean (SD)]: Abemaciclib was 96.3% (1.1) protein bound. Protein binding was similar for the active metabolites M2, M18, and M20. In patients with advanced breast cancer, concentrations of abemaciclib, M2, and M20 in cerebrospinal fluid are comparable to unbound plasma concentrations.
  • Elimination: The mean plasma elimination half-life for abemaciclib was 18.3 hours (72% CV).
  • Metabolism: Abemaciclib is metabolized primarily to M2, M18, and M20 by CYP3A4. These active metabolites are equipotent to abemaciclib and their AUCs accounted for 25%, 13%, and 26% of the total circulating analytes in plasma, respectively. 
  • Excretion: Approximately 81% of the dose was recovered in feces and approximately 3% recovered in urine. The majority of the dose eliminated in feces was metabolites.
Drug Interactions

Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold and may lead to increased toxicity.   

Reduce the VERZENIO dosage with concomitant use of other strong CYP3A inhibitors. See the full prescribing information linked below for specific dosage modifications. Patients should avoid grapefruit products.  Concomitant use with itraconazole (predicted) or clarithromycin (observed) increased the relative potency adjusted unbound AUC of abemaciclib and its active metabolites by 2.2-fold and 1.7-fold, respectively. 

Avoid concomitant use of strong CYP3A inducers and consider alternative agents. Rifampin decreased the plasma concentrations of abemaciclib and its active metabolites by 67% and may lead to reduced activity. 

Use in Specific Populations

No dosage adjustment is needed for age (range 24-91 years), sex, body weight (range 36 175 kg), mild to moderate renal impairment (CLcr ≥ 30-89 mL/min, estimated by Cockcroft-Gault [C-G]), and mild to moderate hepatic impairment (Child-Pugh A or B). The pharmacokinetics of abemaciclib in patients with severe renal impairment (CLcr < 30 mL/min, C-G), end stage renal disease, or in patients on dialysis is unknown.  

Reduce the VERZENIO dosing frequency to once daily in patients with severe hepatic impairment (Child-Pugh C). The relative potency adjusted unbound AUC of abemaciclib and its active metabolites in plasma increased 2.4-fold in subjects with severe hepatic impairment. 

Efficacy and Safety

Efficacy of VERZENIO in combination with fulvestrant was demonstrated in a randomized, placebo-controlled, multicenter study of 669 women with HR-positive, HER2-negative metastatic breast cancer in combination with fulvestrant in patients with disease progression following endocrine therapy who had not received chemotherapy in the metastatic setting. Additional information regarding efficacy studies can be found in the full prescribing information linked below.

The most frequently reported (≥ 5%) Grade 3 or 4 adverse reactions in patients receiving VERZENIO plus fulvestrant were neutropenia, diarrhea, leukopenia, anemia, and infections. Severe (Grade 3 and 4) neutropenia was observed in patients receiving VERZENIO as monotherapy. Most common adverse reactions (incidence ≥ 20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, and thrombocytopenia.

Full prescribing information for VERZENIO is available at https://go.usa.gov/xnqNn.  

Full prescribing information for fulvestrant is available at https://go.usa.gov/xnqP9.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online athttp://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

We always welcome your thoughts regarding the format, content, and utility of the communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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