jueves, 2 de noviembre de 2017

Clinical Pharmacology Corner: FDA Approves CALQUENCE (acalabrutinib)

FDA Approves CALQUENCE (Acalabrutinib) for Adults with Mantle Cell Lymphoma (MCL) 

On October 31, 2017, the U.S. Food and Drug Administration (FDA) approved CALQUENCE for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. The approved recommended dosage of CALQUENCE is 100 mg orally approximately every 12 hours until disease progression or unacceptable toxicity. Patients should swallow the CALQUENCE capsule whole with water.  

Recommended dose modifications for adverse reactions are described in the full prescribing information (link below).

Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD) 
  • MOA :  CALQUENCE is an inhibitor of Bruton’s tyrosine kinase (BTK). 
  • General PK: Acalabrutinib exhibits almost linear PK across a dose range of 75 to 250 mg (0.75 to 2.5 times the approved recommended single dose). 
  • Absorption: The geometric mean absolute bioavailability of acalabrutinib was 25%. Median Tmax was 0.75 hours.
  • Distribution: Reversible binding of acalabrutinib to human plasma protein was 97.5%. Mean blood-to-plasma ratio was 0.7 in vitro. The mean Vss was approximately 34 L. 
  • Elimination: Following a single oral dose of 100 mg acalabrutinib, the median terminal elimination t1/2 was 0.9 (range: 0.6 to 2.8) hours. The t1/2 of the active metabolite, ACP-5862, was 6.9 hours. Acalabrutinib mean apparent oral clearance (CL/F) was 159 L/hr. 
  • Metabolism: Acalabrutinib is predominantly metabolized by CYP3A enzymes, and to a minor extent, by glutathione conjugation and amide hydrolysis. Geometric mean AUC of ACP-5862 was approximately 2- to 3-fold higher than acalabrutinib. ACP-5862 is approximately 50% less potent than acalabrutinib with regard to BTK inhibition.
  • Excretion: Following administration of a single 100 mg radiolabeled acalabrutinib dose in healthy subjects, 84% of the dose was recovered in the feces and 12% of the dose was recovered in the urine, with less than 1% of the dose excreted as unchanged acalabrutinib.
  • PD: Inactivation of BTK occurred throughout the recommended dosing interval in patients with B-cell malignancies.
Drug Interactions
  • Strong CYP3A Inhibitors: Co-administration may increase acalabrutinib concentrations resulting in increased toxicity. Avoid co-administration with strong CYP3A inhibitors. Alternatively, interrupt CALQUENCE dose with short-term co-administration with a strong CYP3A inhibitor (e.g., anti-infective for up to 7 days). 
  • Moderate CYP3A Inhibitors: Co-administration may increase acalabrutinib concentrations resulting in increased toxicity. Reduce CALQUENCE dose to 100 mg once daily when co-administered with moderate CYP3A inhibitors. 
  • Strong CYP3A Inducers: Co-administration may decrease acalabrutinib concentrations resulting in reduced activity. Avoid co-administration with strong CYP3A inducers. If a strong CYP3A inducer cannot be avoided, increase CALQUENCE dose to 200 mg twice daily.
  • Gastric Acid Reducing Agents: Co-administration may decrease acalabrutinib concentrations resulting in reduced activity. Avoid co-administration with proton pump inhibitors (PPIs). Take CALQUENCE 2 hours before taking a H2-receptor antagonist. Separate dosing of antacids and CALQUENCE by at least 2 hours.
Use in Specific Populations

Age (42 to 90 years), sex, race (Caucasian, African American), mild or moderate renal impairment (eGFR ≥ 30 mL/min/1.73 m2), mild or moderate hepatic impairment (total bilirubin 1.5-3 x ULN and any AST), and body weight did not have clinically meaningful effects on acalabrutinib PK. The effect of severe renal impairment (eGFR < 29 mL/min/1.73 m2), renal impairment requiring dialysis, or severe hepatic impairment (Child-Pugh C or total bilirubin 3-10 x ULN and any AST) on acalabrutinib PK is unknown.  

Efficacy and Safety

Efficacy of CALQUENCE at the approved recommended dosage was demonstrated in an open-label, study of patients with MCL who had received at least one prior therapy. The major efficacy outcome was overall response rate. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (reported in ≥ 20% of patients) were anemia, thrombocytopenia, headache, neutropenia, diarrhea, fatigue, myalgia, and bruising.

Full prescribing information is available at https://go.usa.gov/xn2b5

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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