| Reference | 1. J Clin Pharmacol. 2017 Nov;57(11):1425-1431. doi: 10.1002/jcph.944. Epub 2017 Jun
15.
<br>
Lucerastat, an Iminosugar for Substrate Reduction Therapy: Pharmacokinetics,
Tolerability, and Safety in Subjects With Mild, Moderate, and Severe Renal
Function Impairment.
<br>
Guérard N(1), Zwingelstein C(1), Dingemanse J(1).
<br>
Author information: <br>
(1)Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, 4123
Allschwil, Switzerland.
<br>
Lucerastat, an inhibitor of glucosylceramide synthase, has the potential for
substrate reduction therapy in glycosphingolipid storage disorders such as Fabry
disease. In pharmacokinetic studies in rats, dogs, and healthy subjects, the main
route of elimination was renal. The pharmacokinetics, tolerability, and safety of
lucerastat were evaluated in subjects with mild (group A), moderate (group B),
and severe (group C) renal impairment. Group D included healthy subjects.
Thirty-two subjects (8 per group) were included in this single-center, open-label
study and received a single oral dose of 1000 mg lucerastat in groups A and B and
500 mg in groups C and D. The degree of renal impairment of the subjects was
based on estimated glomerular filtration rate. Plasma lucerastat concentrations
(dose-corrected) were higher in groups B and C compared to group D. The
elimination phase half-life was slower in groups B (9.6 hours) and C (16.1 hours)
compared to group D (7.0 hours). Increased exposure to lucerastat was observed in
subjects from groups B and C with ratio of geometric means (90%CI) of 1.60 (1.29,
1.98) for group B vs D and 3.17 (2.76, 3.65) for group C vs D. There were no
clinically relevant abnormalities in vital signs, 12-lead electrocardiograms, and
clinical laboratory values. Four nonserious adverse events were reported by 4
subjects (1 in group A, 3 in group D). Lucerastat was well tolerated in all dose
groups. Dose adjustment is warranted in subjects with moderate and severe renal
impairment.
<br>
2. Clin Pharmacol Ther. 2017 Jul 12. doi: 10.1002/cpt.790. [Epub ahead of print]
<br>
Lucerastat, an Iminosugar for Substrate Reduction Therapy: Tolerability,
Pharmacodynamics, and Pharmacokinetics in Patients With Fabry Disease on Enzyme
Replacement.
<br>
Guérard N(1), Oder D(2), Nordbeck P(2), Zwingelstein C(3), Morand O(4), Welford
RW(5), Dingemanse J(1), Wanner C(2).
<br>
Author information: <br>
(1)Department of Global Clinical Pharmacology, Idorsia Pharmaceuticals Ltd,
Allschwil, Switzerland.
(2)Fabry Center for Interdisciplinary Therapy (FAZiT), Comprehensive Heart
Failure Center (CHFC), and Department of Internal Medicine I, Divisions of
Cardiology and Nephrology, University Hospital Würzburg, Würzburg, Germany.
(3)Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil,
Switzerland.
(4)Department of Global Clinical Science, Idorsia Pharmaceuticals Ltd, Allschwil,
Switzerland.
(5)DD Biology, Translational Science, Idorsia Pharmaceuticals Ltd, Allschwil,
Switzerland.
<br>
Lucerastat is a glucosylceramide synthase inhibitor aimed at reducing production
of glycosphingolipids (GSLs), including those accumulating in Fabry disease. The
safety, tolerability, pharmacodynamics, and pharmacokinetics of oral lucerastat
were evaluated in an exploratory study in patients with Fabry disease. In this
single-center, open-label, randomized study, 10 patients received lucerastat
1,000 mg b.i.d. for 12 weeks in addition to enzyme replacement therapy (ERT; the
lucerastat group). Four patients with Fabry disease received ERT only. Eight
patients reported 17 adverse events (AEs) in the lucerastat group. No clinically
relevant safety abnormalities were observed. The mean (SD) levels of the plasma
GSLs, glucosylceramide, lactosylceramide, and globotriaosylceramide, were
significantly decreased from baseline in the lucerastat group (-49.0% (16.5%),
-32.7% (13.0%), and -55.0% (10.4%), respectively). Lucerastat 1,000 mg b.i.d. was
well tolerated in patients with Fabry disease over 12 weeks. A marked decrease in
plasma GSLs was observed, suggesting clinical potential for lucerastat in
patients with Fabry disease.
<br>
3. Orphanet J Rare Dis. 2017 Jan 14;12(1):9. doi: 10.1186/s13023-017-0565-9.
<br>
Lucerastat, an iminosugar with potential as substrate reduction therapy for
glycolipid storage disorders: safety, tolerability, and pharmacokinetics in
healthy subjects.
<br>
Guérard N(1), Morand O(2), Dingemanse J(3).
<br>
Author information: <br>
(1)Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd,
Gewerbestrasse 16, 4123, Allschwil, Switzerland. [email protected].
(2)Department of Global Clinical Science & Epidemiology, Actelion Pharmaceuticals
Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
(3)Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd,
Gewerbestrasse 16, 4123, Allschwil, Switzerland.
<br>
BACKGROUND: Lucerastat, an inhibitor of glucosylceramide synthase, has the
potential to restore the balance between synthesis and degradation of
glycosphingolipids in glycolipid storage disorders such as Gaucher disease and
Fabry disease. The safety, tolerability, and pharmacokinetics of oral lucerastat
were evaluated in two separate randomized, double-blind, placebo-controlled,
single- and multiple-ascending dose studies (SAD and MAD, respectively) in
healthy male subjects.<br>
METHODS: In the SAD study, 31 subjects received placebo or a single oral dose of
100, 300, 500, or 1000 mg lucerastat. Eight additional subjects received two
doses of 1000 mg lucerastat or placebo separated by 12 h. In the MAD study, 37
subjects received placebo or 200, 500, or 1000 mg b.i.d. lucerastat for 7
consecutive days. Six subjects in the 500 mg cohort received lucerastat in both
absence and presence of food.<br>
RESULTS: In the SAD study, 15 adverse events (AEs) were reported in ten subjects.
Eighteen AEs were reported in 15 subjects in the MAD study, in which the 500 mg
dose cohort was repeated because of elevated alanine aminotransferase (ALT)
values in 4 subjects, not observed in other dose cohorts. No severe or serious AE
was observed. No clinically relevant abnormalities regarding vital signs and
12-lead electrocardiograms were observed. Lucerastat Cmax values were comparable
between studies, with geometric mean Cmax 10.5 (95% CI: 7.5, 14.7) and 11.1 (95%
CI: 8.7, 14.2) μg/mL in the SAD and MAD study, respectively, after 1000 mg
lucerastat b.i.d. tmax (0.5 – 4 h) and t1/2 (3.6 – 8.1 h) were also within the
same range across dose groups in both studies. Using the Gough power model, dose
proportionality was confirmed in the SAD study for Cmax and AUC0-∞, and for
AUC0-12 in the MAD study. Fed-to-fasted geometric mean ratio for AUC0-12 was 0.93
(90% CI: 0.80, 1.07) and tmax was the same with or without food, indicating no
food effect.<br>
CONCLUSIONS: Incidence of drug-related AEs did not increase with dose. No serious
AEs were reported for any subject. Overall, lucerastat was well tolerated. These
results warrant further investigation of substrate reduction therapy with
lucerastat in patients with glycolipid storage disorders. SAD study was
registered on clinicaltrials.gov under the identifier NCT02944487 on the 24th of
October 2016 (retrospectively registered). MAD study was registered on
clinicaltrials.gov under the identifier NCT02944474 on the 25th of October 2016
(retrospectively registered).<br>
TRIAL REGISTRATION: A Study to Assess the Safety and Tolerability of Lucerastat
in Subjects With Fabry Disease. Clinicaltrials.gov: NCT02930655 .
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