A Semi‐Mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy

Abstract

A pharmacokinetic (PK) model was developed for nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3–7 mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain, and pons. The estimated volumes were 13.6, 937, 4.5, 53.8, and 2.11 mL, respectively. Global sensitivity analysis demonstrated that the CSF‐to‐plasma drug distribution rate (0.09 hour−1) is a major determinant of the maximum nusinersen concentration in central nervous system (CNS) tissues. Physiological age‐based and body weight‐based allometric scaling was implemented with exponent values of −0.08 and 1 for the rate constants and the volume of distribution, respectively. Simulations of the scaled model were in agreement with clinical observations from 52 pediatric phase I PK profiles. The developed model can be used to guide the design of clinical trials with ASOs.

Targeting RNA: A Transformative Therapeutic Strategy

“…Simulations using an allometric model agreed with clinical observations from 52 pediatric patients in phase I studies. This finding supports efforts to utilize more sophisticated quantitative models, such as mechanism‐based population PK as a means to guide dose selection and trial design …”

“…Dose selection plays a critical role in the development of oligonucleotide therapeutics. The first‐in‐human dose is generally selected by computational integration of preclinical pharmacology, PK, and toxicology characterization . As mentioned in Pharmacology , the unique mechanism of action of this class of drugs enables straightforward measurement of the effect on mRNA and protein levels in animal models and potential relevance to human disease modulation .…”

“…This finding supports efforts to utilize more sophisticated quantitative models, such as mechanism-based population PK as a means to guide dose selection and trial design. 59 IT delivery through lumbar puncture or use of s.c. IT catheters to circumvent spinal pathology (e.g., scoliosis and spinal fusion) are the common delivery methods of antisense oligonucleotides in the clinic.…”

“…The first-in-human dose is generally selected by computational integration of preclinical pharmacology, PK, and toxicology characterization. 59,68 As mentioned in Pharmacology, the unique mechanism of action of this class of drugs enables straightforward measurement of the effect on mRNA and protein levels in animal models and potential relevance to human disease modulation. 68 Although target tissues are often inaccessible in the clinical setting, the plasma or CSF PK can often serve as a biomarker for target tissue PK (see Pharmacokinetics).…”

Pharmacokinetics and Proceedings in Clinical Application of Nucleic Acid Therapeutics

“…Upon allometric scaling, the NHP model was able to predict drug pharmacokinetics for CSF and plasma in pediatric patients with SMA within acceptable limits. 33 The main mechanism for cleavage of target RNAs is ASO-facilitated RNase H-mediated degradation. In an interesting study, the multipleturnover ability of LNA-based oligonucleotides dependent on the Tm was determined.…”