As you all know natlaizumab is typically dosed at 4 week intervals = standard dose interval. This stops lymphocytes and probably monocytes entering the brain and so stops immune survellience of the brain, exposing people to risks of brain infection with JC virus that causes PML By extending the interval to 6 weeks (extended dosing interval = EDI). This seems to reduce the risk of PML without increasing the risk of relapse. Studies are ongoing…But along came COVID-19 and neuros have adopted EDI to reduce trips to hospital. This paper works of the mechanics of this but trying to work out how long the CD49d alpha 4 integrin target of natalizumab is blocked for based on data from past trials. This suggests that there are no issues if you are less than 80kg in weight, but there may be a risk of relapse in people over 80kg. So maybe ProfG/K and the team can do an audit to see how this has worked out in our clinical practise.
Chang I, Muralidharan KK, Campbell N, Ho PR. Modeling the Efficacy of Natalizumab in Multiple Sclerosis Patients Who Switch From Every-4-Week Dosing to Extended-Interval Dosing [published online ahead of print, 2020 Sep 19]. J Clin Pharmacol. 2020;10.1002/jcph.1737. doi:10.1002/jcph.1737
Natalizumab is approved for multiple sclerosis treatment at a dose of 300 mg every 4 weeks. Extended-interval dosing of natalizumab has been proposed as a strategy to mitigate the risk of progressive multifocal leukoencephalopathy, but the efficacy of extended-interval dosing is not established.
Here, the efficacy of natalizumab extended-interval dosing was modeled specifically in patients switching from every-4-week dosing to extended-interval dosing. Published population pharmacokinetic/pharmacodynamic models were used to simulate the distribution of alpha-4 integrin saturations (blocking of the natalizumab target) for different body weight categories and dosing intervals (every 5, 6, 7, 8, 10, or 12 weeks). Generalized estimating equations relating alpha-4 integrin saturation to probability of multiple sclerosis lesion or relapse were derived from RESTORE trial data, which included patients (n = 175) who discontinued natalizumab after being treated every 4 weeks for ≥1 year and had no relapses in the year before discontinuation. The model-based simulations described indicate that every-5-week or every-6-week dosing is likely to maintain the efficacy of natalizumab, particularly at body weights <80 kg, in patients who switch after a period of stability on every-4-week dosing. The efficacy of natalizumab decreases as dosing intervals and body weight increase. Partial model validation was achieved in that observed outcomes in an independent clinical study were similar to those predicted by the models.
As ProfG aims start his DODO trial, double dose of ocrelizumab, se have to ask why isn’t the size of people taken into account when dosing? Obviously it is easy to give a set dose but if the recipient is a small 40kg person verses someone at 120kg, that is three times the size. Cladribine is the only high efficacy DMT that is doses according to weight. I wonder if ths will occur with natalizumab if EDI becomes the norm. Time and datawill tell