Plavina Tatiana, Muralidharan Kumar Kandadi, Kuesters Geoffrey, Mikol Daniel, Evans Karleyton, Subramanyam Meena, Nestorov Ivan, Chen Yi, Dong Qunming, Ho Pei-Ran, Amarante Diogo, Adams Alison, De Sèze Jerome, Fox Robert, Gold Ralf, Jeffery Douglas, Kappos Ludwig, Montalban Xavier, Weinstock-Guttman Bianca, Hartung Hans-Peter, Cree Bruce A C
From Biogen (T.P., K.K.M., G.K., D.M., K.E., M.S., I.N., Y.C., Q.D., P.-R.H., D.A.), Cambridge, MA; Ashfield Healthcare Communications (A.A.), Middletown, CT; Hôpital Civil (J.D.S.), Strasbourg, France; Mellen Center for Multiple Sclerosis (R.F.), Cleveland Clinic, OH; St. Josef Hospital (R.G.), Ruhr University, Bochum, Germany; Piedmont HealthCare (D.J.), Mooresville, NC; Neurologic Clinic and Policlinic (L.K.), Departments of Medicine, Clinical Research, Biomedicine, and Biomedical Engineering, University Hospital and University of Basel, Switzerland; Vall d'Hebron University Hospital (X.M.), Barcelona, Spain; Jacobs MS Center and Pediatric MS Center of Excellence (B.W.-G.), Jacobs Neurological Institute, Buffalo, NY; Department of Neurology (H.-P.H.), Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany; and University of California San Francisco Multiple Sclerosis Center (B.A.C.C.).
Neurology. 2017 Oct 10;89(15):1584-1593. doi: 10.1212/WNL.0000000000004485. Epub 2017 Sep 15.
To characterize the reversibility of natalizumab-mediated changes in pharmacokinetics/pharmacodynamics in patients with multiple sclerosis (MS) following therapy interruption.
Pharmacokinetic/pharmacodynamic data were collected in the Safety and Efficacy of Natalizumab in the Treatment of Multiple Sclerosis (AFFIRM) (every 12 weeks for 116 weeks) and Randomized Treatment Interruption of Natalizumab (RESTORE) (every 4 weeks for 28 weeks) studies. Serum natalizumab and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured using immunoassays. Lymphocyte subsets, α4-integrin expression/saturation, and vascular cell adhesion molecule-1 (VCAM-1) binding were assessed using flow cytometry.
Blood lymphocyte counts (cells/L) in natalizumab-treated patients increased from 2.1 × 10 to 3.5 × 10. Starting 8 weeks post last natalizumab dose, lymphocyte counts became significantly lower in patients interrupting treatment than in those continuing treatment (3.1 × 10 vs 3.5 × 10; = 0.031), plateauing at prenatalizumab levels from week 16 onward. All measured cell subpopulation, α4-integrin expression/saturation, and sVCAM changes demonstrated similar reversibility. Lymphocyte counts remained within the normal range. Ex vivo VCAM-1 binding to lymphocytes increased until ≈16 weeks after the last natalizumab dose, then plateaued, suggesting reversibility of immune cell functionality. The temporal appearance of gadolinium-enhancing lesions was consistent with pharmacodynamic marker reversal.
Natalizumab's effects on peripheral immune cells and pharmacodynamic markers were reversible, with changes starting 8 weeks post last natalizumab dose; levels returned to those observed/expected in untreated patients ≈16 weeks post last dose. This reversibility differentiates natalizumab from MS treatments that require longer reconstitution times. Characterization of the time course of natalizumab's biological effects may help clinicians make treatment sequencing decisions.
This study provides Class III evidence that the pharmacodynamic markers of natalizumab are reversed ≈16 weeks after stopping natalizumab.
描述那他珠单抗介导的药代动力学/药效学变化在多发性硬化症（MS）患者治疗中断后的可逆性。
在那他珠单抗治疗多发性硬化症的安全性和有效性（AFFIRM）研究（每12周进行一次，共116周）和那他珠单抗随机治疗中断（RESTORE）研究（每4周进行一次，共28周）中收集药代动力学/药效学数据。使用免疫测定法测量血清那他珠单抗和可溶性血管细胞粘附分子-1（sVCAM-1）。使用流式细胞术评估淋巴细胞亚群、α4整合素表达/饱和度和血管细胞粘附分子-1（VCAM-1）结合情况。
接受那他珠单抗治疗的患者血液淋巴细胞计数（细胞/L）从2.1×10增加到3.5×10。从最后一剂那他珠单抗给药后8周开始，中断治疗的患者淋巴细胞计数显著低于继续治疗的患者（3.1×10对3.5×10；P = 0.031），从第16周起稳定在产前那他珠单抗水平。所有测量的细胞亚群、α4整合素表达/饱和度和sVCAM变化均显示出相似的可逆性。淋巴细胞计数保持在正常范围内。体外VCAM-1与淋巴细胞的结合在最后一剂那他珠单抗给药后约16周前增加，然后趋于平稳，表明免疫细胞功能具有可逆性。钆增强病变的时间出现与药效学标志物逆转一致。
那他珠单抗对外周免疫细胞和药效学标志物的作用是可逆的，变化从最后一剂那他珠单抗给药后8周开始；在最后一剂给药后约16周，水平恢复到未治疗患者中观察到/预期的水平。这种可逆性使那他珠单抗与需要更长恢复时间的MS治疗方法区分开来。那他珠单抗生物学效应时间进程的特征描述可能有助于临床医生做出治疗顺序决策。
本研究提供了III类证据，表明那他珠单抗的药效学标志物在停止使用那他珠单抗后约16周逆转。
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