NEW YORK (Reuters Health) - In multiple sclerosis (MS) patients treated with natalizumab, the risk of developing progressive multifocal leukoencephalopathy (PML) does not appear to be associated with high blood levels of the drug, preliminary research from the Netherlands suggests.
"Natalizumab very effectively treats MS, but its use is limited by the rare but possibly lethal complication of PML," said Dr. Zoe van Kempen of the MS Center at the Vrije Universiteit (VU) Medical Center in Amsterdam.
"In five PML patients, we did not find higher natalizumab serum concentrations before they developed PML compared to 10 controls," she told Reuters Health by email. "This contradicts the hypothesis that lowering natalizumab exposure could be protective of the complication PML."
The findings were published online December 13 in Multiple Sclerosis Journal.
Dr. van Kempen and her colleagues followed a cohort of 219 patients with relapsing-remitting multiple sclerosis (RRMS) who were treated with natalizumab (NTZ) at one academic medical center. Over about 10 years, five patients developed PML and were matched with 10 patients who did not.
The PML patients received a mean of 43 NTZ infusions compared to 106 in the control group; serum samples were collected every 12 weeks prior to each patient's infusion.
The mean NTZ concentration was 18.9 mcg/mL in the PML patients before the condition was diagnosed and 23.8 mcg/mL in the 10 controls. "Neither the patients who developed PML nor the controls showed a relevant rise in serum concentrations over time," the researchers write.
Dr. van Kempen cautioned, "The number of patients in our study was too small to draw definite conclusions. Even so, with these negative results, we want to inform our colleagues of a possible overstatement of the risk reduction when extending natalizumab infusion intervals with the aim of decreasing the risk of PML."
Dr. Bianca Weinstock-Guttman, who directs the Jacobs Multiple Sclerosis Center for Treatment and Research at the University at Buffalo, New York, noted that "measuring NTZ levels may not provide a safeguard" against PML.
"While the preliminary benefit for increasing the interval between the infusions may be related to dose vs. saturation, the study may suggest that the saturation is probably more important than the levels," she told Reuters Health by email.
Dr. Weinstock-Guttman advised doctors to maintain close monitoring in patients treated with NTZ.
Dr. Claire Riley, director of the Multiple Sclerosis Clinical Care and Research Center at Columbia University Medical Center in New York City, told Reuters Health by email, "There seems to be increased risk of PML in individuals with lower body mass, suggesting a role of medication concentration. While the natalizumab blood levels were similar in those who did and did not develop PML, this study doesn't answer the question of whether a lower blood level (achieved by lower dosing, which could be by weight or with less frequency of same dose) might lower the risk of PML."
Dr. Riley noted that optimal NTZ dosing is not well established and she recommended further research to explore potential alternative dosing strategies.
Dr. Arun Venkatesan, director of the Johns Hopkins Encephalitis Center at Johns Hopkins University School of Medicine in Baltimore, Maryland, said, "The results are not altogether surprising for a number of reasons, including: 1) serum concentrations of NTZ may not accurately reflect concentrations in the brain blood vessels; 2) there are likely to be complex genetic differences between individuals that account for the effects of NTZ in promoting PML and that do not correlate precisely with drug concentrations."
"Strengths of the study included multiple time points at which serum was collected from patients, while a major limitation was the small number of patients who developed PML, thus limiting conclusions," he told Reuters Health by email.
Dr. van Kempen and her colleagues are now conducting a larger multicenter trial in the Netherlands to explore the effect of extending natalizumab infusion intervals. Dr. Weinstock-Guttman is involved in this work.
The study did not have commercial funding.
Mult Scler J 2016.
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