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1145 Effects of L-Glutamine on Biomarkers of Response in Sickle Cell Disease: A Pharmacokinetics-Pharmacodynamics Analysis

Program: Oral and Poster Abstracts
Session: 114. Sickle cell Disease, Sickle Cell Trait and Other Hemoglobinopathies, Excluding Thalassemias: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Sickle Cell Disease, adult, Non-Biological therapies, Hemoglobinopathies, pediatric, Diseases, Therapies, young adult , Pharmacology, Study Population, Human
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Alina Sadaf, MBBS1, Min Dong, PhD2*, Jennifer Korpik1*, Amanda Pfeiffer1*, Theodosia A. Kalfa, MD, PhD3, Teresa S. Latham, MA1*, Alexander A. Vinks, PharmD, PhD, FCP4*, Russell E. Ware, MD, PhD1 and Charles T. Quinn, MD, MS5

1Division of Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
2Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
3Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
4Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
5Division of Hematology, Cincinnati Children's Hospital Med. Ctr., Cincinnati, OH

Oral L-glutamine (Endari®) has been approved by the US-FDA to reduce the acute complications of sickle cell disease (SCD) in patients at least 5 years of age. L-glutamine has several roles in the body including de novo synthesis of intracellular glutathione which acts as an antioxidant. However, the mechanisms of action by which L-glutamine could reduce complications in SCD require further investigation. Additionally, there are no known biomarkers to assess response to L-glutamine therapy.

We conducted an open-label, dose-ascending trial (NCT04684381) of L-glutamine in pediatric (n=4) and adult (n=4) participants with SCD as well as in adult healthy volunteers (n=4) (Table 1). Over a three-week trial period with 4 study visits, serial blood samples were collected to define the pharmacokinetics (PK), pharmacodynamics (PD), and PK-PD interactions of L-glutamine using a broad panel of laboratory investigations including amino acid concentrations, blood counts, percentage of dense red blood cells (%DRBC), whole blood viscosity, osmotic and oxygen gradient ektacytometry, and reactive oxygen species (ROS) of reticulocytes (ROSretic) and mature red blood cells (ROSRBC).

In PK-PD analysis of amino acids, we focused analysis on arginine (Arg), citrulline (Cit), and ornithine (Orn) based on the hypothesis that L-glutamine improves endothelial function by increasing arginine bioavailability and augmenting nitric oxide (NO) production. Peak arginine concentration was directly correlated with both the maximum L-glutamine concentration (Cmax, p=0.001) and area-under-the curve (AUC) (p=0.047) indicating improvement in arginine bioavailability, but there was no significant linear correlation with either the Arg:Orn or Arg:(Orn+Cit) ratios.

In PK-PD analysis of osmotic gradient ektacytometry, L-glutamine Cmax was directly correlated with the elongation maximum (EImax), noted in all participants at visit 4 (p=0.033). In SCD participants, L-glutamine Cmax was inversely correlated with Ohyper (osmolality at EImax/2) at visits 3 (p=0.044) and 4 (p=0.004). In PK-PD analysis of oxygen gradient ektacytometry in SCD participants, L-glutamine Cmax was inversely correlated with the point of sickling (POS) at visit 3 (p=0.005) but not at visit 4 (p=0.054). Together, these findings suggest that although L-glutamine may decrease cellular hydration (decreased Ohyper) it may increase RBC deformability (increased EImax) and delay the onset of sickling after hypoxia (decreased POS).

In PK-PD analysis of viscometry, higher L-glutamine Cmax was associated with higher whole blood viscosity measurements at all shear rates (p<0.05). However, L-glutamine Cmax was also directly correlated with hematocrit-to-viscosity ratio (HVR) at the highest shear rates in the overall population at visit 4 (p<0.05). In addition, L-glutamine Cmax for SCD participants was associated with increased hemoglobin concentration, an effect that was observed at visit 4 (p=0.025), and increased %DRBC, an effect detected at visits 3 (p=0.008) and 4 (p=0.007).

In PK-PD analysis of ROS, L-glutamine AUC was inversely correlated with ROSRetic (p=0.024), but not ROSRBC, in all participants at visit 3. When considered as total ROSRetic (calculated as ROSretic × absolute reticulocyte count), there was a similar inverse correlation with glutamine AUC in SCD participants, although not statistically significant. In contrast to all other biomarkers, L-glutamine Cmax was not correlated with any ROS measurement.

This PK-PD analysis of L-glutamine reveals biological effects that alter RBC characteristics and could modify SCD-related complications, with a complex interplay summarized in Figure 1. Prospective studies can validate these biomarkers and be used to monitor the effects of L-glutamine therapy in SCD patients.

Disclosures: Kalfa: Forma/Novo Nordisk: Consultancy, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. Latham: Emmaus Medical: Research Funding. Ware: Emmaus Medical: Research Funding; Addmedica: Research Funding. Quinn: Emmaus Medical: Research Funding.

*signifies non-member of ASH