RESUMEN
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.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Antibacterianos/farmacocinética , Ceftriaxona/farmacocinética , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Ceftriaxona/administración & dosificación , Ceftriaxona/uso terapéutico , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Distribución TisularRESUMEN
OBJECTIVES: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. METHODS: In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. RESULTS: Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. CONCLUSIONS: The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. TRIAL REGISTRATION: ClinicalTrials.gov NCT00349622.
Asunto(s)
Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Antibacterianos/uso terapéutico , Ceftriaxona/uso terapéutico , Proyectos de Investigación , Esclerosis Amiotrófica Lateral/sangre , Esclerosis Amiotrófica Lateral/líquido cefalorraquídeo , Antibacterianos/efectos adversos , Antibacterianos/sangre , Antibacterianos/farmacocinética , Ceftriaxona/efectos adversos , Ceftriaxona/sangre , Ceftriaxona/farmacocinética , Demografía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
This retrospective analysis of preclinical and clinical radiolabeled immunoglobulin studies focuses on three well-known observations: (1) IV tumor reactive IgG provides higher response rates in patients with hematological malignancies than in patients with solid tumors. (2) Patients with CD20 positive B cell lymphoma require a high IV IgG protein dose for effective tumor targeting. (3) Most patients experience high uptake of IV administered radiolabeled IgG in normal liver. This review supports the following new hypotheses: (1) The blood-tumor barrier in most solid tumors is higher than in most hematological malignancies. (2) The blood-tumor barrier in CD20 positive B cell lymphomas is lowered by the IV administration of high doses [> 100 mg] of anti-CD20 IgG, presumably due to IgG induced intra-tumoral production of vaso-active biological response modifiers. (3) The blood-tumor barrier is low in Hodgkin's disease, presumably due to the continuous and innate production of biological response modifiers in tissues containing Hodgkin's disease. (4) The uptake of tumor reactive IgG in the normal liver is controlled by the Fc portion of the IgG. The radioimmunoconjugate is not catabolized in the liver. This appears to indicate that the F(c) portion of the IgG binds to the MHC class I like, F(c)gammaRn receptors in liver endothelium and hepatocytes and not to F(c)gamma RI, RII or RIII receptors The new hypotheses require verification and can be instrumental in the design of new more effective clinical RIT studies.