Eliglustat for Gaucher Disease: Quantifying the Impact of Pharmacogenetic Status on DDIs
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.