Neurol Neuroimmunol Neuroinflamm 2019 Sep 1;6(5). Epub 2019 Jul 1.
From the Multiple Sclerosis Study Center (A.G.), ASST Valle Olona, Gallarate Hospital (VA); Department of Neurology (G.C., L.M.), Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan; Department of Neurology (L.M.G.), Fondazione Istituto G. Giglio, Cefalù; Department of Neurology (C.P.), "La Sapienza" University, Rome; Biogen Italia (S.F.), Milan; and Department of Neuroscience DNS, Multiple Sclerosis Centre (P.G.), Università degli Studi di Padova, Italy.
Objective: This phase I study investigated pharmacokinetic (PK) and pharmacodynamic (PD) profiles of natalizumab in pediatric patients with relapsing-remitting MS (RRMS).
Methods: Pediatric patients with RRMS who were prescribed natalizumab 300 mg IV every 4 weeks were enrolled. Blood samples were collected on days 1, 2, 8, 15, and 22 and at weeks 4, 8, 12, and 16 to estimate PK parameters; PD properties were evaluated by measuring α4-integrin saturation and lymphocyte counts over time. Natalizumab's safety profile was also evaluated.
Results: PK parameters were similar to those reported in adult patients; natalizumab concentrations peaked approximately 1 day after infusion in most of the participants (Cmax 142.9 μg/mL, AUClast 47389.4 hr*μg/mL), followed by a biphasic decline with a rapid distribution phase and a slow elimination phase, with a terminal half-life of 215.1 hours. In terms of PD, both time course and magnitude of α4-integrin saturation and increase in lymphocyte counts were similar to those observed in adults. During the 16-week study follow-up, 3 adverse events attributed to natalizumab were observed; no unexpected safety events occurred.
Conclusions: PK profile, α4-integrin saturation, lymphocyte counts, and safety observed in these pediatric patients are comparable to those reported in adults.
Classification Of Evidence: This study provides Class I evidence that natalizumab PK/PD parameters and safety profile are similar in adults and pediatric patients in the short term. Longer studies, also including a larger number of younger subjects (aged 10-12 years), are required to further inform about long-term PK and PD parameters in pediatric patients with MS.