A Population Pharmacokinetic Analysis of L -Glutamine Exposure in Patients with Sickle Cell Disease: Evaluation of Dose and Food Effects

Background and Objective l -Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of l -glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on l -glutamine exposure in patients with sickle cell disease compared to normal participants. Methods We conducted an open-label dose-ascending trial of l -glutamine in pediatric and adult participants with sickle cell disease ( N = 8) and adult healthy volunteers ( N = 4), providing a total of 400 plasma l -glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma l -glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed. Results l -glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) l -glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral l -glutamine. A covariate analysis showed that baseline l -glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that l -glutamine can be taken with or without food. Conclusions We report the first pharmacokinetic study of multiple-dose, long-term oral l -glutamine therapy and the first population pharmacokinetic analysis of l -glutamine for sickle cell disease. These findings may permit optimized dosing of l -glutamine for patients with sickle cell disease to maximize treatment benefits. Clinical Trial Registration This trial is registered at ClinicalTrials.gov (NCT04684381).