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

Yanli Zhao, Merit E. Cudkowicz, Jeremy M. Shefner, Lisa Krivickas, William S. David, Francine Vriesendorp, Alan Pestronk, James B. Caress, Jonathan Katz, Ericka Simpson, Jeffrey Rosenfeld, Robert Pascuzzi, Jonathan Glass, Kourosh Rezania, Jerold S. Harmatz, David Schoenfeld, David J. Greenblatt

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1180-1187
Number of pages8
JournalJournal of clinical pharmacology
Volume54
Issue number10
DOIs
StatePublished - Oct 2014

Keywords

  • HPLC micromethod
  • amyotrophic lateral sclerosis
  • ceftriaxone
  • cerebrospinal fluid uptake
  • plasma pharmacokinetics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Zhao, Y., Cudkowicz, M. E., Shefner, J. M., Krivickas, L., David, W. S., Vriesendorp, F., Pestronk, A., Caress, J. B., Katz, J., Simpson, E., Rosenfeld, J., Pascuzzi, R., Glass, J., Rezania, K., Harmatz, J. S., Schoenfeld, D., & Greenblatt, D. J. (2014). Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis. Journal of clinical pharmacology, 54(10), 1180-1187. https://doi.org/10.1002/jcph.317