Using PBPK for Label Recommendations in Rare Disease: Deflazacort for Duchenne Muscular Dystrophy

Deflazacort (Emflaza®) was fast-tracked, given orphan status, and approved by the US FDA in February 2017 for patients 5 years and older with Duchenne Muscular Dystrophy (DMD). Emflaza is a corticosteroid that works by decreasing inflammation and reducing the activity of the immune system. It is also a pro-drug, which undergoes conversion in the plasma by esterases, taken to the liver and metabolized by CYP3A4 enzymes. Not only did this raise a concern about the drug’s drug-drug interaction (DDI) liability, but DMD patients typically take multiple other medicines to support the heart, breathing muscles, bone health, gastrointestinal symptoms, hormone levels, common antibiotics, and to manage pain.

The Simcyp Pediatric Simulator was used to model exposure in children and adolescents, simulate DDIs, and provide dose recommendations. Dose adjustments for moderate to severe CYP3A4 inhibitors and inducers were determined using the physiologically-based pharmacokinetic (PBPK) modeling as described in the label.

CS Certara Using PBPK for Label Recommendations

FDA writes in a recently published paper, “Approximately 60% of the intended uses of PBPK in regulatory decision making are related to drug-drug interaction. The PBPK predictions for the drug drug interaction in children and adolescents, such as the interaction with concomitant administration of CYP3A modulators, have been accepted as supportive evidence for the proposed dosing recommendations on the deflazacort label.”

DMD is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four years, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis followed by the arms, which can result in trouble standing up. Scoliosis is also common. Females with a single copy of the defective gene may show mild symptoms.

CS Certara Using PBPK for Label Recommendations 2

도움이 필요하신가요?

문의하기