Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis

The cephalosporin antibiotic ceftriaxone was evaluated as a potential therapeutic agent for the treatment of amyotrophic lateral sclerosis (ALS). The pharmacokinetics (PK) of ceftriaxone in plasma and cerebrospinal fluid (CSF) were investigated in 66 participants in a previously reported clinical trial. Their mean age was 51 years, and 65% were male. Participants were randomly assigned to 1 of 3 treatment groups receiving intravenous infusions (mean duration: 25-minutes) every 12-hours of either: placebo and placebo; 2-g ceftriaxone and placebo; or 2-g ceftriaxone twice. Mean steady-state plasma PK variables were: volume of distribution, 14-L (0.17-L/kg); elimination half-life, 8-9-h; total clearance, 17-21-mL/min (0.22-0.25-mL/min/kg). Values were not different between dosage groups. CSF PK analysis, determined through sparse CSF sampling, indicated apparent entry and elimination half-life values of 1.0 and 34-hours, respectively. With both dosage regimens, CSF concentrations were maintained above the target threshold of 1.0-μM (0.55-μg/mL) as determined from in vitro models. The plasma and CSF PK profiles of ceftriaxone were used as a basis for planning the Phase 3 clinical trial of ceftriaxone in ALS.