title: Exposure-disease response analysis of natalizumab in subjects with multiple sclerosis.
abstract: Natalizumab, a human immunoglobulin monoclonal antibody that targets α4β1/α4β7integrin, is an effective therapy approved for the treatment of multiple sclerosis (MS). The objective of this analysis was to develop a population exposure-response model utilizing gadolinium-enhancing (Gd) lesion count data from four clinical studies and annualized relapse rate (ARR) data from three clinical studies. The natalizumab exposures were derived for the individuals using a population pharmacokinetic model. A log-linear exposure effect on Gd lesion count and ARR adequately characterized the relationship between exposure and disease response. In the case of the Gd lesion count model, a bimodal model that distributed subjects into two subpopulations based on low or high baseline Gd lesion count provided a superior goodness of fit. The mean (95% confidence interval) slopes from the exposure-Gd lesion count model and exposure-ARR model are -0.0903 (-0.100, -0.081) and -0.0222 (-0.026, -0.015) (mg/L)-1, respectively. From these slopes, it can be inferred that both Gd lesion count and ARR decrease with increasing exposure to natalizumab in MS subjects. Model-based simulations demonstrated that although reductions in Gd lesion count and ARR were observed with lower doses (75, 150, or 200 mg), only the dose of 300 mg every 4 weeks (q4w) was associated with an ARR ≤0.25 and was considered clinically effective. The results from the exposure-Gd lesion count and exposure-ARR models thus support the appropriateness of the approved natalizumab dose (300 mg q4w) in MS subjects.
authors.affiliation: Systems Pharmacology, Biogen, 14 Cambridge Center, Cambridge, MA, 02142, USA.
authors.forename: Kumar Kandadi
authors.initials: KK
authors.lastname: Muralidharan
authors.affiliation: Clinical Development, Biogen, Cambridge, MA, USA.
authors.forename: Deb
authors.initials: D
authors.lastname: Steiner
authors.affiliation: Global Medical Affairs, Biogen, Cambridge, MA, USA.
authors.forename: Diogo
authors.initials: D
authors.lastname: Amarante
authors.affiliation: Global Medical Affairs, Biogen, Cambridge, MA, USA.
authors.forename: Pei-Ran
authors.initials: PR
authors.lastname: Ho
authors.affiliation: Clinical Development, Biogen, Cambridge, MA, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Mikol
authors.affiliation: Clinical Development, Biogen, Cambridge, MA, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Elkins
authors.affiliation: Global Biomarker Discovery and Development, Biogen, Cambridge, MA, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Subramanyam
authors.affiliation: Systems Pharmacology, Biogen, 14 Cambridge Center, Cambridge, MA, 02142, USA. ivan.nestorov@biogen.com.
authors.forename: Ivan
authors.initials: I
authors.lastname: Nestorov
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D005260:Female; D005682:Gadolinium / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism; D000069442:Natalizumab / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab; D005682:Gadolinium
keywords: Annualized relapse rate; Gadolinium-enhancing; Multiple sclerosis; Once-every-4-weeks dosing regimen; Pharmacokinetics