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.
Program in Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA, USA.
Yanli
Y
Zhao
Merit E
ME
Cudkowicz
Jeremy M
JM
Shefner
Lisa
L
Krivickas
William S
WS
David
Francine
F
Vriesendorp
Alan
A
Pestronk
James B
JB
Caress
Jonathan
J
Katz
Ericka
E
Simpson
Jeffrey
J
Rosenfeld
Robert
R
Pascuzzi
Jonathan
J
Glass
Kourosh
K
Rezania
Jerold S
JS
Harmatz
David
D
Schoenfeld
David J
DJ
Greenblatt
D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002443:Ceftriaxone / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D014018:Tissue Distribution
D000900:Anti-Bacterial Agents; D002443:Ceftriaxone
HPLC micromethod; amyotrophic lateral sclerosis; ceftriaxone; cerebrospinal fluid uptake; plasma pharmacokinetics