Intrathecal administration of recombinant human superoxide dismutase 1 in amyotrophic lateral sclerosis: A preliminary safety and pharmacokinetic study

We undertook a safety and pharmacokinetic study of intrathecal (IT) recombinant human superoxide dismutase (rhSOD1). We administered rhSOD1 as an acute bolus in three sheep and 16 human subjects with amyotrophic lateral sclerosis (ALS). Two sheep received chronic IT infusion of rhSOD1 (one at 17.7 mg per day, the second at 38.0 mg per day) for six months. Two of the 16 subjects had familial ALS and mutations in the gene for Cu/Zn SOD1. They both received IT infusion of rhSOD1 (5 to 10 mg per day) for 3 to 6 months. Intrathecal rhSOD1 administration was safe. Bolus IT administration of 0.25 mg rhSOD1 in sheep revealed a mean elimination half-life of 0.4 (SD +/- 0.06) hours, clearance of 12.2 +/- 3.2 ml per hour, and volume of distribution of 7.3 +/- 0.9 ml. After chronic IT infusion, the initial alpha-phase half-life was estimated as 1.2 hours and the extended beta-phase half-life was 15.0 hours. The mean clearance rate was 25.9 ml per hour and the steady-state volume of distribution was 920.6 ml. Bolus IT administration of 20 mu g of rhSOD1 in ALS subjects revealed a mean elimination half-life of 2.2 +/- 0.8 hours, clearance of 1.2 +/- 0.6 ml per hour, and volume of distribution of 3.5 +/- 0.4 ml, With chronic IT infusion of 5 mg per day, cerebrospinal SOD1 levels increased approximately fortyfold. We detected no benefit of this treatment in the two patients with familial ALS.