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Systemic pharmacokinetics and cerebrospinal fluid uptake of intravenous ceftriaxone in patients with amyotrophic lateral sclerosis
Author(s) -
Zhao Yanli,
Cudkowicz Merit E.,
Shefner Jeremy M.,
Krivickas Lisa,
David William S.,
Vriesendorp Francine,
Pestronk Alan,
Caress James B.,
Katz Jonathan,
Simpson Ericka,
Rosenfeld Jeffrey,
Pascuzzi Robert,
Glass Jonathan,
Rezania Kourosh,
Harmatz Jerold S.,
Schoenfeld David,
Greenblatt David J.
Publication year - 2014
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.317
Subject(s) - ceftriaxone , pharmacokinetics , medicine , placebo , cerebrospinal fluid , volume of distribution , anesthesia , amyotrophic lateral sclerosis , antibiotics , pharmacodynamics , cephalosporin , gastroenterology , pharmacology , chemistry , pathology , biochemistry , alternative medicine , disease
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.