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

Abstract

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).

Fig. 1

Study schema.l-glutamine dosing regimen and pharmacokinetic studies are shown by study visit. PK pharmacokinetics

Fig. 2

Pharmacokinetic profiles of l-glutamine and l-glutamate. Mean (± standard deviation) concentrations of l-glutamine (black) and glutamate (blue) are shown by time (hours) after the first dose of study medication for each visit. Study visits are arranged by columns, and study groups (1 = pediatric sickle cell disease, 2 = adult sickle cell disease, and 3 = healthy volunteers) are arranged in rows. The baseline glutamine concentrations from visit 1 are shown by the dotted red line in all graphs to demonstrate the return to baseline concentrations across multiple doses

Fig. 3

l-glutamine peak concentration (C_max) normalized by dose. Dose-normalized C_max decreased with dose escalation, indicating capacity-limited non-linear pharmacokinetics of oral l-glutamine

Fig. 4

Prediction-corrected visual predictive check of the final population pharmacokinetic model. The x-axis indicates time after the baseline glutamine concentration. The y-axis is the prediction-corrected glutamine concentration. Individual data points are shown in small open figures in black. The red line is the median of the observed data. The dashed black lines show the 2.5th and 97.5th percentiles of the observed data. The area shaded light red shows the 95% confidence interval of the model-predicted median. The area shaded in gray shows the 95% confidence interval of the model-predicted 2.5th and 97.5th percentiles