A phase I, pharmacokinetic, dosage escalation study of creatine monohydrate in subjects with amyotrophic lateral sclerosis

Abstract

Creatine monohydrate (creatine) has potential neuroprotective properties and is a commonly used supplement in amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Minimum therapeutic and maximum tolerated dosages of creatine are not yet known, nor is it known what systemic plasma concentrations result from specific dosage regimens. The objectives of this study were to establish steady-state plasma pharmacokinetics of creatine at several dosages, and to evaluate the effects of creatine on brain metabolites using proton magnetic resonance spectroscopy ((1)H-MRS). Six participants with ALS received creatine at three weekly escalating oral dosages (5, 10, and 15 g b.i.d.). Plasma creatine levels and MR spectra were obtained at baseline and with each dosage increase. Mean pre-dose steady-state creatine plasma concentrations were 20.3, 39.3, and 61.5 ug/ml at 5, 10, and 15 g b.i.d., respectively. Creatine spectra increased by 8% (p = 0.06) and glutamate + glutamine signals decreased by 17% (p = 0.039) at higher dosages. There were no safety concerns at any of the dosages. In conclusion, creatine plasma concentrations increased in a dose-dependent manner. Creatine appears to cross the blood-brain barrier, and oral administration of 15 g b.i.d. is associated with increased in vivo brain creatine concentrations and decreased glutamate concentrations.

Figure 1

Mean (± SE) plasma concentrations of creatine (left) and creatinine (right) among the six patients at corresponding times.

Figure 2

Percent change in Cr and Glx. Percent changes in creatine (Cr) concentrations (left) and glutamate + glutamine (Glx) concentrations (right) observed by in vivo MR spectroscopy in the frontal cortex over the course of creatine monohydrate treatment.

Figure 3

Change in metabolite spectrum. Magnetic resonance spectra of one of the subjects showing increased creatine + phosphocreatine (Cr) and decreased glutamine and glutamate (Glx) concentrations after treatment with creatine 15 g/day.

Figure 4

Percent change in metabolites. Percent changes in creatine + phosphocreatine (tCr), glutamate + glutamine concentrations (Glx) N-acetyl aspartate (NAA) myo-inositol (MI) and choline (Cho) observed by in vivo MR spectroscopy between pretreatment and 15 g b.i.d. creatine dosage.

Figure 5

Percent change in metabolites over choline. Percent changes in creatine + phosphocreatine (tCr), glutamate + glutamine concentrations (Glx) N-acetyl aspartate (NAA) and myo-inositol (MI) as ratios over choline (Cho) observed by in vivo MR spectroscopy between baseline and 15 g b.i.d. creatine dosage.