Janneke M. Brussee, Dominik Lott, Markus S. Müller, Patricia N. Sidharta, Jasper Dingemanse, Andreas Krause
Idorsia Pharmaceuticals Ltd, Department of Clinical Pharmacology, Allschwil, Switzerland
Introduction/Objectives: Lucerastat is an iminosugar molecule with the potential to provide substrate reduction therapy for the treatment of Fabry disease (FD), an inherited X-linked lysosomal storage disorder [1]. Multiple studies have been performed evaluating safety, tolerability, efficacy, and pharmacokinetics (PK) in healthy subjects and patients with FD, including a Phase 1 study in subjects with mild, moderate, and severe renal function impairment, as 85% of unchanged lucerastat is eliminated via the kidneys [1, 2]. The objective was to develop a population model describing the PK of lucerastat, including the effects of demographics, renal function, and differences between subjects with and without FD.
Methods: Data from six Phase 1 studies in healthy subjects and two Phase 3 studies in patients with FD were pooled for analysis. These included single-dose administration of 100 to 4000 mg and multiple-dose administration of 200 to 1000 mg lucerastat b.i.d. The modelling data set comprised 5312 lucerastat concentration measurements from 250 (151 without, 99 with FD) subjects. A population PK model was developed using non-linear mixed effects modelling techniques. Parameters were estimated using SAEM in Monolix 2020R1. Age, body weight, sex, race, renal function, concomitant therapy with enzyme replacement therapy, food intake, and effect of FD were investigated in a covariate analysis for their impact on model parameters. Since renal function drives elimination of lucerastat, variables depicting renal function, i.e., plasma creatinine concentration, creatinine clearance, and estimated glomerular filtration rate (eGFR) were extensively evaluated, with power functions and Emax models to describe the covariate-clearance relationship. Deterministic simulations were performed in a typical FD-patient of 70 kg with different eGFR values to quantify the differences in PK between a fixed dosing regimen of 1000 mg b.i.d. and the eGFR-based dose reductions in the Phase 3 studies, i.e., with normal to mildly impaired eGFR (mL/min/1.73 m2) ≥ 60: 1000 mg b.i.d., ≥ 45 and < 60: 750 mg b.i.d., ≥ 30 and < 45: 500 mg b.i.d.
Results:
The PK of lucerastat were well described by a 2-compartment model, linear clearance, and first-order absorption including a short lag time of 0.077 h (4.6 min). Allometric scaling of all clearance and volume parameters was included. Correlation between renal function and lucerastat clearance was better described by eGFR than by plasma creatinine concentration or creatinine clearance. The final model included eGFR as Emax function on clearance, with an estimated E50 of 88.6 mL/min/1.73m2 and a Hill factor of 1.39. Compared to subjects without FD, patients with FD had a 32% lower plasma clearance and a 71% lower apparent peripheral volume. There was no evidence of differences in absorption rate or lag time due to food intake.
Without eGFR-based dose reductions, the model predicted a 1.62- and 2.30-fold exposure (AUC), 1.39- and 1.82-fold maximum concentration (Cmax), and 2.28- and 3.75-fold trough concentration (Ctrough) at steady state in a typical FD patient with an eGFR of 50 and 35 mL/min/1.73 m2, respectively, compared to a patient with an eGFR of 90 mL/min/1.73 m2 following a fixed dosing regimen of 1000 mg b.i.d. When doses were reduced to 750 and 500 mg b.i.d. for subjects with eGFR of 45-60 and 30-45 mL/min/1.73 m2, respectively, AUC, Cmax, and Ctrough were similar (i.e., 1.21 and 1.15-fold, 1.04- and 0.91-fold, and 1.71- and 1.87-fold, respectively, compared to subjects with normal function or mild impairment eGFR > 60 mL/min/1.73 m2), with the largest increase in Ctrough.
Conclusions: Body weight, renal function as reflected by eGFR, and disease (with and without FD) were included as covariates in the population PK model, with renal function being the most clinically relevant. The suggested eGFR-based dose reductions of lucerastat in subjects with moderately to severely impaired renal function are adequate, leading to similar PK profiles and exposure metrics in patients with FD with normal renal function and different degrees of renal function impairment. The model provides a robust basis to support interactions with health authorities via model-based simulations.
References:
[1] Guérard N et al. Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects. Orphanet J Rare Dis. 2017 Jan 14;12(1):9.
[2] Guérard N et al. Lucerastat, an iminosugar for substrate reduction therapy: pharmacokinetics, tolerability, and safety in subjects with mild, moderate, and severe renal function impairment. J Clin Pharmacol. 2017 Nov;57(11):1425-1431.
Reference: PAGE 30 (2022) Abstr 10005 [www.page-meeting.org/?abstract=10005]
Poster: Drug/Disease Modelling - Other Topics