Population pharmacokinetics-based recommendations for a single delayed or missed dose of nusinersen

MacCannell, Drew; Berger, Zdenek; East, Lilly; Kirschner, Janbernd; Muntoni, F.; Farrar, Michelle A.; Peng, Joanna; Zhou, Jie; Nestorov, Ivan; Farwell, Wildon; Finkel, Richard S.

doi:10.1016/j.nmd.2021.02.014

Cited by 15 publications

(37 citation statements)

References 17 publications

(16 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This results in a stable CSF exposure across a wide range of body weights, while the exposure in the plasma compartment reduces significantly as body weight increases. The detailed results from the model parameters have been reported previously [ 32 ].…”

Section: Methodsmentioning

confidence: 99%

“…Simulations of treatment interruptions were performed in accordance with previously published analyses that evaluated shorter delays in nusinersen dosing during the loading or maintenance phases [ 32 ]. The Fisher information matrix and the interindividual variability measures of all relevant parameters were sampled to produce an ensemble of 10,000 unique parameter sets.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported [ 32 ] two scenarios of dosing delays during the maintenance regimen: a short delay (defined as < 4 months) and one missed maintenance dose. If a delay in administration occurs, nusinersen levels will be restored rapidly by administering the delayed dose as soon as possible and then administering the subsequent dose as previously scheduled.…”

Section: Introductionmentioning

confidence: 99%

“…If a delay in administration occurs, nusinersen levels will be restored rapidly by administering the delayed dose as soon as possible and then administering the subsequent dose as previously scheduled. If one maintenance dose is missed, nusinersen levels will be restored most rapidly by administering the missed dose as soon as possible, followed by an additional dose 14 days later [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…A longer treatment interruption may occur in the context of clinical practice for a number of reasons, such as the ongoing COVID-19 pandemic, pregnancy/childbirth, or changing therapy and subsequently returning to nusinersen. Similar to our previous report [ 32 ], this analysis is based on a population pharmacokinetic (PK) model, given the limited data from clinical trials on dosing delays. Because of the different potential reasons for treatment interruptions, all dosing intervals are expressed as time since the last dose was administered.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2022

Self Cite

View full text Add to dashboard Cite

show abstract

Scientific rationale for a higher dose of nusinersen

Finkel

Ryan

Pascual

et al. 2022

Ann Clin Transl Neurol

Self Cite

View full text Add to dashboard Cite

Objective: The long-term favorable safety profile of nusinersen provides an opportunity to consider a higher dose. We report on the relationships between nusinersen cerebrospinal fluid (CSF) exposure, biomarker levels, and clinical efficacy. Methods: The analyses used data from the CS3A and ENDEAR studies of nusinersen in participants with infantile-onset spinal muscular atrophy (SMA). Steady-state CSF trough (C trough ) levels, plasma phosphorylated neurofilament heavy chain (pNF-H) levels, body weight, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores were selected as parameters of interest. A validated population pharmacokinetic (PK) model was applied to predict the nusinersen CSF C trough . PK/pharmacodynamic (PK/PD) models used nusinersen CSF C trough measurements, which were time-matched with CHOP INTEND scores. Results: Higher nusinersen CSF exposure was associated with a greater decrease in pNF-H levels and greater efficacy, as measured by change in the CHOP INTEND score from baseline. These findings indicate a dose-response relationship between CSF nusinersen levels and treatment response. The higher dose is predicted to lead to approximately a 2.4-fold increase in nusinersen CSF levels with fewer loading doses. PK/PD modeling indicates that a higher concentration of nusinersen may predict an additional 5-point increase in CHOP INTEND score beyond that observed with 12 mg. Interpretation: Our data indicate that a higher dose of nusinersen may lead to additional clinically meaningful improvement in efficacy when compared with the currently approved 12-mg dose. The efficacy, safety, and PK of a higher nusinersen dose are currently under investigation in the ongoing phase 2/3 DEVOTE study (NCT04089566).

show abstract

Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5‐year update of theNURTUREstudy

et al. 2023

Self Cite

View full text Add to dashboard Cite

Introduction/Aims NURTURE (NCT02386553) is an open‐label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow‐up (data cut: February 15, 2021) are reported. Methods The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety. Results Median age of children was 4.9 (3.8–5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies. Discussion These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

show abstract

Population pharmacokinetics-based recommendations for a single delayed or missed dose of nusinersen

Cited by 15 publications

References 17 publications

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

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

Scientific rationale for a higher dose of nusinersen

Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5‐year update of theNURTUREstudy

Contact Info

Product

Resources

About