Population pharmacokinetic analysis of sparsentan in healthy volunteers and patients with focal segmental glomerulosclerosis

Autor: Russell Wada, Huub Jan Kleijn, Lu Zhang, Shang‐Chiung Chen
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: CPT: Pharmacometrics & Systems Pharmacology, Vol 12, Iss 8, Pp 1080-1092 (2023)
Druh dokumentu: article
ISSN: 2163-8306
DOI: 10.1002/psp4.12996
Popis: Abstract Sparsentan is a single‐molecule dual endothelin angiotensin receptor antagonist (DEARA) currently under investigation as a treatment for focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN). A population pharmacokinetic (PK) analysis was performed to characterize the PKs of sparsentan and to evaluate the impact of FSGS disease characteristics and co‐medications as covariates on sparsentan PKs. Blood samples were collected from 236 healthy volunteers, 16 subjects with hepatic impairment, and 194 primary and genetic FSGS patients enrolled in nine studies ranging from phase I to phase III. Sparsentan plasma concentrations were determined using validated liquid chromatography–tandem mass spectrometry with a lower limit of quantitation of 2 ng/mL. Modeling was conducted with the first‐order conditional estimation with η–ϵ interaction (FOCE‐1) method in NONMEM. A total of 20 covariates were tested using a univariate forward addition and stepwise backward elimination analysis with significance level of p
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