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Exposure–disease response analysis of natalizumab in subjects with multiple sclerosis
- Source :
- Journal of Pharmacokinetics and Pharmacodynamics. 44:263-275
- Publication Year :
- 2017
- Publisher :
- Springer Science and Business Media LLC, 2017.
-
Abstract
- Natalizumab, a human immunoglobulin monoclonal antibody that targets α4β1/α4β7 integrin, 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.
- Subjects :
- Adult
Male
medicine.medical_specialty
Multiple Sclerosis
Adolescent
Exposure disease
Disease Response
Population
Gadolinium
Antibodies, Monoclonal, Humanized
Gastroenterology
α4β7 integrin
Young Adult
03 medical and health sciences
0302 clinical medicine
Natalizumab
Pharmacokinetics
Recurrence
Internal medicine
medicine
Humans
030212 general & internal medicine
education
Aged
Pharmacology
Clinical Trials as Topic
education.field_of_study
business.industry
Multiple sclerosis
Middle Aged
medicine.disease
Confidence interval
Treatment Outcome
Immunology
Female
business
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 15738744 and 1567567X
- Volume :
- 44
- Database :
- OpenAIRE
- Journal :
- Journal of Pharmacokinetics and Pharmacodynamics
- Accession number :
- edsair.doi.dedup.....6f5bad6ce0fa1a854509e0c9b49d2f98