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: Q = 0.572 L/h, Q = 0.069 L/h, CL = 2.50 L/h, CL = 0.133 L/hr, V = 0.441 L, V = 32.0 L, V = 429 L, and V = 258 L. A full covariate modeling approach identified baseline body weight to be a statistically and clinically relevant covariate on V , V , and CL . 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.

Lumbosacral and thoracolumbosacral cerebrospinal fluid volume changes in neonates, infants, children, and adolescents: A retrospective magnetic resonance imaging study

“…Recently, nusinersen, a novel intrathecal therapeutic agent for spinal muscular atrophy was introduced . However, because there were no previous studies describing the spinal CSF volume of pediatric patients, age‐based dose scaling of nusinersen trials were determined based on the age‐to‐brain CSF volume relationship reported by Matsuzawa et al Thus, along with the brain CSF volume, the spinal CSF volumes in the present study can be used for a more accurate prediction of the total CSF volume in pediatric patients. However, other factors such as the fluid dynamics of CSF, lipid solubility and baricity, and the drugs themselves must be considered to understand the pharmacokinetics and pharmacodynamic characteristics of intrathecal medication…”

“…Additionally, we calculated both LS‐CSF volume and TLS‐CSF volume in pediatric patients for the first time. As LS‐CSF volume is one of the most important factors during spinal anesthesia and TLS‐CSF volume can be used to assess the pharmacokinetics of intrathecal medications, the results from this study will be helpful in understanding these issues of pediatric intrathecal medications.…”

“…Most drugs are administered intravenously or orally, but some are administered intrathecally. Intrathecal medications include local anesthetics, antibiotics, antineoplastics, analgesics, antispasticity agents, and antisense oligonucleotides . In this situation, cerebrospinal fluid (CSF) volume can have a significant effect on the pharmacokinetics and pharmacodynamics of intrathecally administered drugs.…”

“…The lumbosacral CSF (LS‐CSF) volume can affect intrathecal local anesthetics for spinal anesthesia. In addition, thoracolumbosacral CSF (TLS‐CSF) volume can affect intrathecal chemotherapy, and the administration of other novel intrathecal medications, such as antisense oligonucleotides for treating neurological disorders …”

Targeting RNA: A Transformative Therapeutic Strategy

“…In humans, the apparent volume of distribution in the CSF was estimated for nusinersen using a population PK analysis . The estimate was greater than the CSF volume, suggesting significant distribution into CNS tissues.…”