miércoles, 2 de agosto de 2017

Clinical Pharmacology Corner: FDA Approves IDHIFA (enasidenib)

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FDA Approves IDHIFA® (Enasidenib) for Treatment of Adults with Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-2 Mutation

On August 1, 2017, the U.S. Food and Drug Administration (FDA) approved IDHIFA (enasidenib) for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. Information on FDA-approved tests is available at http://www.fda.gov/CompanionDiagnostics.
The approved recommended dose is 100 mg once daily with or without food until disease progression or unacceptable toxicity. For patients without disease progression or unacceptable toxicity, treat for a minimum of 6 months to allow time for clinical response. Assess patient blood counts and blood chemistries for leukocytosis and tumor lysis syndrome prior to the initiation of IDHIFA and monitor at least every 2 weeks for at least the first 3 months during treatment. Manage any abnormalities promptly. Dosage modifications for patients with toxicity are described in the full prescribing information (link below).
Mechanism of Action (MOA), General Pharmacokinetics (PK), and Pharmacodynamics (PD)
  • MOA: Enasidenib is an inhibitor of the IDH2 enzyme.
  • Dose Proportionality: The area under concentration time curve (AUC) of enasidenib increases in an approximately dose proportional manner. 
  • Accumulation: Approximately 10-fold when administered once daily.
  • Absorption: The absolute bioavailability of enasidenib is approximately 57%. The median time to Cmax (Tmax) is 4 hours after a single 100 mg oral dose.
  • Plasma Protein Binding: Enasidenib 98.5% and AGI-16903 metabolite (active) 96.6%, in vitro.
  • Terminal Half-Life (mean): 137 hours (CV% 41) for enasidenib.
  • Metabolism (In Vitro): Enasidenib by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, UGT1A1, UGT1A3, UGT1A4, UGT1A9, UGT2B7, and UGT2B15 and AGI-16903 metabolite by CYP1A2, CYP2C19, CYP3A4, UGT1A1, UGT1A3, and UGT1A9. 
  • Excretion: Approximately 89% of the total recovered radiolabeled enasidenib dose was eliminated in the feces and 11% was eliminated in the urine. Unchanged enasidenib recovery was 34% in the feces and negligible in the urine.
  • Cardiac Electrophysiology: Enasidenib did not prolong the QT interval to a clinically relevant extent.
Drug Interactions 
Clinical drug interaction studies of IDHIFA have not been conducted. Based upon in vitro studies, coadministration of IDHIFA may increase or decrease the concentrations of combined hormonal contraceptives. The clinical significance of this potential drug interaction is unknown at this time.
Use in Specific Populations
The following population characteristics were not associated with a clinically significant effect on the pharmacokinetics of enasidenib: Age (19 to 100 years), sex, race (White, Black, Asian), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1.0 to 1.5 times ULN and any AST), renal impairment (creatinine clearance ≥ 30 mL/min by Cockcroft-Gault), body weight (39 kg to 136 kg), and body surface area. 
Efficacy and Safety
The clinical efficacy and safety of IDHIFA were demonstrated at the recommended dosage in an open-label, single-arm trial that enrolled 199 adult patients with relapsed or refractory AML with an IDH2 mutation. Additional information regarding the efficacy trials can be found in the full prescribing information linked below. The most common adverse reactions (AR) of IDHIFA were nausea, vomiting, diarrhea, elevated bilirubin, and decreased appetite. The most common serious ARs were leukocytosis, diarrhea, nausea, vomiting, decreased appetite, tumor lysis syndrome, and differentiation syndrome. 

Full prescribing information is available at https://go.usa.gov/xRPEY.
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. 
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 at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or 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 burst was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

FDA/Center for Drug Evaluation and Research (CDER)
Office of Translational Sciences
Office of Clinical Pharmacology
Email: ocp@fda.hhs.gov

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