viernes, 23 de diciembre de 2016

Clinical Pharmacology Corner: FDA Approves RUBRACA (Rucaparib)

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FDA Approves RUBRACATM (Rucaparib) for Advanced Ovarian Cancer with Deleterious BRCA Mutation

On December 19, 2016, the U.S. Food and Drug Administration (FDA) approved RUBRACATM(rucaparib) for the monotherapy treatment of patients with deleterious BRCA mutation-associated advanced ovarian cancer who have been treated with two or more chemotherapies. Select patients for therapy based on an FDA-approved companion diagnostic for RUBRACA. The approved recommended dosage of RUBRACA is 600 mg taken orally twice daily with or without food.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD)
MOA: Rucaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor which plays a role in DNA repair.
Absorption: The median Tmax was 1.9 hours at the approved recommended dosage. The mean absolute bioavailability of rucaparib immediate-release tablet was 36% with a range from 30% to 45%.
Food Effect: Following a high-fat meal, Cmax was increased by 20%, and AUC was increased by 38%.
Dose Proportionality: Rucaparib demonstrated linear PK over a dose range from 240 mg (0.4 times the approved recommended dosage) to 840 mg (1.4 times the approved recommended dosage) taken orally twice daily suggesting time-independence and dose-proportionality.
Plasma Protein Binding: In vitro, the protein binding of rucaparib was 70% in human plasma at therapeutic concentrations.
Accumulation: Systemic exposure accumulation of rucaparib was 3.5 to 6.2 fold at steady state.
Elimination: Median terminal half-life (T1/2) was 17 hours. The apparent clearance ranged from 15.3 to 79.2 L/hour, following continuous 600 mg rucaparib orally twice daily.
Metabolism: Rucaparib was metabolized primarily by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4, in vitro.
Cardiac Electrophysiology: The mean QTcF increase from baseline at steady state of 600 mg rucaparib twice daily was 14.9 msec (90% CI [11.1-18.7]).
Use in Specific Populations
No starting dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin less than or equal to upper limit of normal [ULN] and AST greater than ULN, or total bilirubin between 1.0 to 1.5 times ULN and any AST) or patients with mild to moderate renal impairment (creatinine clearance [CLcr] between 30 and 89 mL/min, as estimated by the Cockcroft-Gault method). No dose recommendation can be made for patients with moderate to severe hepatic impairment (total bilirubin great than 1.5 times ULN) or severe renal impairment (CLcr less than 30 mL/min) due to a lack of data. Exposure differences across CYP2D6 or CYP1A2 genotype subgroups did not differ significantly based on population PK analyses.
Efficacy and Safety
In two multicenter, single-arm, open-label clinical trials, the efficacy population of 106 women with advanced ovarian cancer and at least two prior chemotherapies was treated with RUBRACA 600 mg orally twice daily as monotherapy. The objective response rate by investigator assessment was 54% (57/106; 95% CI: 44-64%), with a median duration of response of 9.2 months (95% CI: 6.6, 11.6). Myelodysplastic syndrome/acute myeloid leukemia was reported in 2 of 377 (0.5%) patients with ovarian cancer treated with RUBRACA. The most common adverse reactions (greater than or equal to 20%) experienced by patients were nausea, fatigue (including asthenia), vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. Adverse reactions led to dose discontinuation in 10% of patients, most frequently from fatigue/asthenia (2%). The median duration of treatment was 5.5 months (ranging from 0.1 to 28.0).

Full prescribing information for RUBRACA is available at
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, by faxing (1-800-FDA-0178), or by 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 (

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This bulletin was prepared by Jinzhong Liu, Ph.D., Clinical Pharmacology Reviewer, Division of Clinical Pharmacology V, 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

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