In 2014, Eliglustat (Cerdelga®) was approved by the FDA as the first long-term treatment for adults with type 1 Gaucher disease. Eliglustat is an oral inhibitor of glucosylceramide synthase. It is metabolized primarily by CYP2D6, and to a lesser extent by CYP3A4. Eliglustat is also an inhibitor of CYP2D6 and is both a substrate and inhibitor of P-gp. As a high clearance drug, the model needed to consider both CYP2D6 phenotypes and genotypes, as well as the time-dependency of CYP2D6 inhibition. Physiologically-based pharmacokinetic (PBPK) modeling and simulation were used extensively to understand and quantify the impact of metabolizer status (extensive, intermediate, or poor) and concomitant medications on eliglustat exposure—as well as the effect that eliglustat has on other drugs—and guide the specific dose adjustment recommendations and labeling language.
Another example of a best practices case study shared by FDA, the impact of the PBPK model for eliglustat was huge because a number of clinical studies that would have to be performed to assess/inform all of the drug-drug interaction (DDI) scenarios were eliminated. The DDI is dependent on both the dose and CYP2D6 phenotype: the CYP2D6 impact changes with the dose, therefore affecting DDI liability.
PBPK simulations informed the labeling for 12 DDIs and dosing recommendations. Labeling recommendations were incorporated based on modeling without the need for additional trials.
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