Nephrology · Medical Literature
Population Pharmacokinetic Modeling for the Iminosugar Lucerastat Supports Dose Adaptation in Patients With Fabry Disease and Moderate to Severe Renal Function Impairment.
Abstract
Lucerastat is an iminosugar with the potential to provide substrate reduction therapy for the treatment of Fabry disease (FD), an inherited X-linked lysosomal storage disorder. The aims of this study were to develop a population pharmacokinetic (PK) model describing lucerastat plasma concentration over time, to investigate the relationships between subject-specific characteristics and model parameters, and to assess the influence of these differences between subjects on lucerastat exposure via model-based simulations. Longitudinal nonlinear mixed effects modeling was applied to develop a model based on data from 250 participants in six Phase 1 and two Phase 3 studies. Lucerastat pharmacokinetics were described by a two-compartment model with linear first-order absorption and elimination, including allometric scaling of body weight on clearance and volume parameters. Lucerastat clearance was reduced in subjects with lower estimated glomerular filtration rate (eGFR). Disease status (with/without FD) was found to impact clearance and volumes of distribution to a limited extent. The model described the data well across the dose range from 100 to 4000 mg. Body weight, disease status, and renal function were shown to influence exposure, with dose adaptation only required in patients with renal function impairment, as body weight and disease status had limited impact. Dose adaptation as applied in Phase 3 (i.e., eGFR [mL/min/1.73 m2] ≥60: 1000 mg; ≥45 and <60: 750 mg; ≥30 and <45: 500 mg; ≥15 and <30: 250 mg b.i.d.) resulted in achieving similar exposure in study participants with FD with different levels of renal function impairment.
Clinical relevance
Fabry disease (FD), an X-linked lysosomal storage disorder, frequently causes progressive nephropathy leading to moderate-to-severe renal impairment, which complicates pharmacotherapy due to altered drug clearance. Lucerastat, a novel iminosugar substrate reduction therapy, requires rigorous pharmacokinetic (PK) characterization across the spectrum of renal function to ensure safe and efficacious dosing in this population. This population PK analysis directly informs evidence-based dose adaptation strategies for FD patients with renal impairment, a clinically critical and underserved subgroup.
Key findings
1. A two-compartment model with linear first-order absorption and elimination, incorporating allometric scaling of body weight on clearance and volume parameters, best described lucerastat PK across a wide dose range (100–4000 mg bid). 2. The model was developed using longitudinal nonlinear mixed-effects modeling (NONMEM) applied to data from 250 participants across six Phase 1 and two Phase 3 studies, providing a robust, multi-study dataset. 3. Estimated glomerular filtration rate (eGFR) was identified as a statistically significant covariate on lucerastat clearance, with lower eGFR corresponding to reduced clearance and consequently increased drug exposure. 4. Disease status (FD vs. healthy subjects) and body weight were found to influence clearance and volumes of distribution, but only to a limited extent, and did not independently necessitate dose adjustment. 5. Model-based simulations confirmed that the eGFR-stratified dosing regimen used in Phase 3 (eGFR ≥60: 1000 mg; ≥45 to <60: 750 mg; ≥30 to <45: 500 mg; ≥15 to <30: 250 mg, all bid) successfully normalized lucerastat exposure across renal function strata in FD patients. 6. No dose adaptation was deemed necessary based on body weight or FD disease status alone, as their impact on PK parameters was not clinically meaningful per simulation outputs.
Practice implications
Clinicians prescribing lucerastat to patients with Fabry disease should implement eGFR-guided dose reduction using the Phase 3-validated stepwise regimen (1000 mg bid for eGFR ≥60 mL/min/1.73 m², down to 250 mg bid for eGFR 15–<30 mL/min/1.73 m²) to achieve comparable systemic exposure regardless of renal function stage. Routine monitoring of renal function (eGFR) is essential, as disease progression-related decline in GFR will necessitate prospective dose re-evaluation over time. Body weight and FD disease status do not require independent dose modification, simplifying the prescribing algorithm to renal function as the sole actionable PK covariate.