Restoration of Nusinersen Levels Following Treatment Interruption in People With Spinal Muscular Atrophy: Simulations Based on a Population Pharmacokinetic Model

Abstract

Background Nusinersen is approved for the treatment of spinal muscular atrophy. The most common approved dosing regimen is four intrathecal loading doses of nusinersen 12 mg; the first three are administered at 14-day intervals followed by a fourth dose 30 days later, and then 12-mg maintenance doses are administered every 4 months thereafter. Interruption of nusinersen treatment in the maintenance dosing phase might occur for a number of clinical reasons. Objective The objective of this report is to describe dosing regimens that allow for the most rapid restoration of steady-state concentrations of nusinersen in the cerebrospinal fluid (CSF) following a treatment interruption during maintenance dosing. Methods Population pharmacokinetic models using integrated pharmacokinetic data from ten nusinersen clinical trials that included a broad range of participants with spinal muscular atrophy treated with intrathecal nusinersen were used to investigate different durations of treatment interruptions during maintenance treatment. Potential dosing regimens for re-initiation of nusinersen were evaluated, with the goal of achieving the quickest restoration of steady-state nusinersen CSF concentrations without exceeding maximal CSF exposures observed during the initial loading period. Results Our pharmacokinetic modeling indicates the following regimen will lead to optimal restoration of nusinersen CSF levels after treatment interruption: two doses of nusinersen should be administered at 14-day intervals following treatment interruptions of ≥ 8 to < 16 months since the last dose, and three doses of nusinersen at 14-day intervals for treatment interruptions of ≥ 16 to < 40 months since the last maintenance dose, with subsequent maintenance dosing every 4 months in both instances. After treatment interruptions of ≥ 40 months, the full loading regimen will rapidly restore nusinersen CSF levels. Conclusions Prolonged treatment interruptions lead to suboptimal CSF levels of nusinersen. The optimal regimen to restore nusinersen CSF levels depends on the interval since the last maintenance dose was administered.

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…The subsequent dose may then be maintained according to the previously defined schedule. Detailed advice based on clinical trial analysis and pharmacokinetic studies is available 152 and is reassuring that only prolonged omission of eight months or more should require additional dosing.…”

Examining Real-World Adherence to Nusinersen for the Treatment of Spinal Muscular Atrophy Using Two Large US Data Sources

“…In the event that patients do miss a dose of nusinersen, population pharmacokinetic modeling has shown that nusinersen levels can be rapidly restored following a dose delay of up to 4 months in the maintenance phase of treatment. This is done by administering the delayed dose as soon as possible; then, the subsequent dose is administered according to the original scheduled date, as long as these two doses are administered at least 14 days apart, followed by a dose every 4 months thereafter [ 30 , 32 ]. For a second or third loading dose delayed by 30–90 days, it is recommended to resume the loading dose as soon as feasible and shift all remaining doses by the same number of days delayed [ 30 ].…”

Effects of the COVID-19 Pandemic on SMA Screening and Care: Physician and Community Insights

“… Local sites for the collection of blood samples, or mobile collection at patients’ homes [ 34 , 44 , 46 ]. A plan for how to maintain the treatment administration schedule whenever possible while preserving patient safety [ 29 , 30 , 47 ]. Remote physical therapy sessions [ 43 , 48 ].…”

“…A plan for how to maintain the treatment administration schedule whenever possible while preserving patient safety [ 29 , 30 , 47 ].…”