PBPK Model Development, Validation, and Application for Prediction of Eliglustat Drug-Drug Interactions

The objectives of this study were: (1) to develop and validate an eliglustat physiologically based pharmacokinetic (PBPK) model with and without drug interactions, (2) to simulate untested DDI scenarios, and (3) to explore potential dosing flexibility using lower doses of eliglustat (commercially not available). PK data from healthy adults receiving eliglustat with or without interacting drugs were obtained from literature and used for the PBPK model development and validation. The model-predicted single dose and steady-state Cmax and AUC of eliglustat were within 50-150% of the observed values when eliglustat was administered alone or co-administered with ketoconazole or paroxetine. Then as model-based simulations, we illustrated eliglustat exposure as a victim of interaction when co-administered with fluvoxamine following the FDA dosing recommendations. Second, we showed that with lower eliglustat doses (21mg, 42mg QD) the exposure in patients of intermediate and poor metabolizer phenotypes was within the outlined safety margin (Cmax < 250ng/mL) when eliglustat was administered with ketoconazole, where the current recommendation is a contraindication of co-administration (84mg). The present study demonstrated that patients with CYP2D6 deficiency may benefit from lower doses of eliglustat.PMID:36056771 | DOI:10.1002/cpt.2738

Source: Clinical Pharmacology and Therapeutics - September 3, 2022 Category: Drugs & Pharmacology Authors: Siddhee A Sahasrabudhe Shen Cheng Mahmoud Al-Kofahi Jeanine R Jarnes Neal J Weinreb Reena V Kartha Source Type: research