sábado, 19 de diciembre de 2015

Clinical Pharmacology Corner Update: FDA Approves ALECENSA (alectinib)

Clinical Pharmacology Corner Banner

FDA Approves ALECENSA® (alectinib) for Anaplastic Lymphoma Kinase (ALK)–positive, Metastatic Non-Small Cell Lung Cancer (NSCLC)
On December 11, 2015, the United States Food and Drug Administration (FDA) approved ALECENSA (alectinib) for the treatment of patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib. The recommended dose of ALECENSA is 600 mg orally twice daily (BID) with food until disease progression or unacceptable toxicity.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)
  • MOA: Alectinib and its major active metabolite M4 are tyrosine kinase inhibitors that target ALK and RET. M4 is a major circulating metabolite with similar in vitro potency and activity to alectinib.
  • Dose proportionality: Alectinib exhibited dose-proportional increases in systemic exposure over the dose range of 460 mg to 900 mg (i.e., 0.75 times to 1.5 times the approved recommended dosage).
  • Accumulation: The geometric mean accumulation is ~6-fold for both alectinib and M4 at steady-state.
  • Plasma protein binding: Both alectinib and M4 are greater than 99% bound to human plasma proteins and independent of plasma concentrations.
  • Terminal half-life (mean): The geometric mean elimination half-life is 33 hours for alectinib and 31 hours for M4.
  • Metabolism: Alectinib undergoes metabolism by CYP3A4 to its major active metabolite M4; the geometric mean metabolite to parent exposure ratio at steady-state concentrations is about 0.40. M4 is subsequently metabolized by CYP3A4.
  • Excretion: Ninety-eight percent of the radioactivity was excreted in feces following oral administration of a single radiolabeled dose of alectinib under fed conditions. Eighty-four percent of the dose was excreted as unchanged alectinib and 6% of the dose was excreted as M4. Excretion of radioactivity in urine was less than 0.5% of administered radiolabeled dose of alectinib.
  • Exposure-efficacy and Exposure-safety: No significant exposure-response (E-R) relationships were identified for the best overall response (BOR), BOR in the central nervous system (CNS), grade 3 or higher adverse events, serious adverse events or adverse events of special interest of any grade at a dose of 600 mg BID.
Drug Interaction Potential
  • No clinically meaningful effect on the combined exposure of alectinib plus M4 was observed in clinical studies following co-administration of ALECENSA with a strong CYP3A inhibitor (posaconazole), a strong CYP3A inducer (rifampin), or an acid-reducing agent (esomeprazole).
  • No clinically meaningful effect on the exposure of midazolam (sensitive CYP3A substrate) or repaglinide (sensitive CYP2C8 substrate) is expected following co-administration with ALECENSA.
Use in Specific Populations
No dose adjustment is recommended for patients with mild and moderate renal impairment or with mild hepatic impairment (defined by National Cancer Institute). Age, body weight, mild hepatic impairment, mild to moderate renal impairment (CLcr 30 to 89 mL/min), race (White, Asian and Other), and sex had no clinically meaningful effect on the systemic exposure of alectinib and M4. The pharmacokinetics of alectinib has not been studied in patients with severe renal impairment, end-stage renal disease or moderate to severe hepatic impairment. 
Safety and Efficacy
The safety and efficacy of ALECENSA were established in two single-arm, multicenter clinical trials conducted in patients with locally advanced metastatic ALK-positive NSCLC, who have progressed on crizotinib. The objective response rate (ORR) was 38% (95% CI: 28%, 49%) by IRC and 46% (95% CI: 35%, 57%) by Investigator for patients in study 1 after a median follow-up of 4.8 months and 44% (95% CI: 36%, 53%) by IRC and 48% (95% CI: 39%, 57%) by Investigator for patients in study 2 after a median follow-up of 10.9 months. The median duration of response was 7.5 months (95% CI: 4.9, not estimable (NE)) by IRC and NE (95% CI: 4.9, NE) by Investigator for Study 1 and was 11.2 months (95% CI: 9.6, NE) by IRC and 7.8 months (95% CI: 7.4, 9.2) for study 2.
An assessment of the ORR and duration of response for central nervous system (CNS) metastases was completed in 51 patients with measurable lesions in the CNS at baseline enrolled into these studies. The ORR in the central nervous system was 61% (95% CI: 46%, 74%) with a median duration of response of 9.1 months (95% CI: 5.8, NE).
The most common adverse reactions (incidence ≥ 20%) were fatigue, constipation, edema and myalgia. Warning and Precautions include hepatotoxicity, interstitial lung disease/pneumonitis, bradycardia, severe myalgia and creatine phopsphokinase elevation and embryo-fetal toxicity.

Full prescribing information is available at http://go.usa.gov/ckX7b.
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).
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/ckXH2).
We always welcome your thoughts regarding the format, content, and utility of information you receive via this Burst email initiative. 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

No hay comentarios:

Publicar un comentario