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Lookup NU author(s): Professor Michela GuglieriORCiD
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© 2024, The American College of Clinical Pharmacology.Human genetic variation (polymorphisms) in genes coding proteins involved in the absorption, distribution, metabolism, and elimination (ADME) of drugs can have a strong effect on drug exposure and downstream efficacy and safety outcomes. Vamorolone, a dissociative steroidal anti-inflammatory drug for treating Duchenne muscular dystrophy (DMD), primarily undergoes oxidation by CYP3A4 and CYP3A5 and glucuronidation by UDP-glucuronosyltransferases. This work assesses the pharmacokinetics (PKs) of vamorolone and sources of interindividual variability (IIV) in 81 steroid-naïve boys with DMD aged 4 to <7 years old considering the genetic polymorphisms of CYPS3A4 (CYP3A4*22, CYP3A4*1B), CYP3A5 (CYP3A5*3), and UGT1A1 (UGT1A1*60) utilizing population PK modeling. A one-compartment model with zero-order absorption (Tk0, duration of absorption), linear clearance (CL/F), and volume (V/F) describes the plasma PK data for boys with DMD receiving a wide range of vamorolone doses (0.25–6 mg/kg/day). The typical CL/F and V/F values of vamorolone were 35.8 L/h and 119 L, with modest IIV. The population Tk0 was 3.14 h yielding an average zero-order absorption rate (k0) of 1.16 mg/kg/h with similar absorption kinetics across subjects at the same vamorolone dose (i.e., no IIV on Tk0). The covariate analysis showed that none of the genetic covariates had any significant impact on the PKs of vamorolone in boys with DMD. Thus, the PKs of vamorolone is very consistent in these young boys with DMD.
Author(s): Li X, Sabbatini D, Pegoraro E, Bello L, Clemens P, Guglieri M, van den Anker J, Damsker J, McCall J, Dang UJ, Hoffman EP, Jusko WJ
Publication type: Article
Publication status: Published
Journal: The Journal of Clinical Pharmacology
Year: 2024
Pages: epub ahead of print
Online publication date: 29/04/2024
Acceptance date: 27/03/2024
ISSN (print): 0091-2700
ISSN (electronic): 1552-4604
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/jcph.2446
DOI: 10.1002/jcph.2446
PubMed id: 38682893
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