title: Population Pharmacokinetics of Nusinersen in the Cerebral Spinal Fluid and Plasma of Pediatric Patients With Spinal Muscular Atrophy Following Intrathecal Administrations.
abstract: Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices. The typical population parameters were: Qp= 0.572 L/h, QCSF= 0.069 L/h, CLp= 2.50 L/h, CLCSF= 0.133 L/hr, VCSF= 0.441 L, Vp= 32.0 L, Vsystemic_tissue= 429 L, and VCNS_tissue= 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on VCSF, Vp, and CLp. The model predicted that the CSF volume of distribution increased steadily with age from 0 to 2 years but became relatively steady for children >2 years. Simulations from the final model showed that age-based dosing in children under 2 years ensured a more comparable exposure (peak concentration and area under the concentration-time curve) across subjects in the population relative to a fixed dosing scheme. However, because no dose-limiting toxicity has been reported in any of the trials, a fixed-dose scheme (12 mg across all age groups) was recommended. The median terminal half-life of nusinersen in the CSF was determined from the model to be 163 days, which supported infrequent dosing, once every 4 to 6 months in pediatric patients with spinal muscular atrophy.
authors.affiliation: Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Kenneth T
authors.initials: KT
authors.lastname: Luu
authors.affiliation: Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Norris
authors.affiliation: Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Rudy
authors.initials: R
authors.lastname: Gunawan
authors.affiliation: Nonclinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Henry
authors.affiliation: Clinical Development, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Geary
authors.affiliation: Pharmacokinetics and Clinical Pharmacology, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006207:Half-Life; D006801:Humans; D007223:Infant; D007278:Injections, Spinal; D008297:Male; D008954:Models, Biological; D009134:Muscular Atrophy, Spinal / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000378:metabolism; D009841:Oligonucleotides / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D009841:Oligonucleotides; C000590926:nusinersen
keywords: Spinraza; cerebral spinal fluid; intrathecal administration; nusinersen; population pharmacokinetics; spinal muscular atrophy