L-Glutamine for Pediatric Sickle Cell Disease: Pharmacology, Mechanism of Action, Safety and Efficacy

Background/Aim: L-Glutamine (L-Gln) has been approved for the treatment of sickle cell disease (SCD) since 2017. Clinical and pharmacological data in pediatric patients remain limited. This review summarizes studies of L-Gln use in SCD including pharmacokinetics (PK), pharmacodynamics (PD), safety, and efficacy in pediatrics, alongside in-vitro and pre-clinical data elucidating primary and supplemental mechanisms of action (MOA). Pharmacoeconomics (PE) is addressed briefly. Materials and Methods: Literature search included keywords of SCD, L-Gln, and pediatrics – targeting papers with PK, PD, PE, clinical and preclinical studies. Thirty-two articles meeting the selection criteria were included for descriptive and analytical review. Results: Two mouse studies were identified. The remaining articles included translational, Phase-2 and Phase-3 trials and studies containing pharmacological data. Pharmacokinetics showed serum L-Gln levels to peak at 800-1000 μM within 1 h after oral intake of clinically relevant doses. Thereafter, approximately 500-600 μM levels were shown to last 4-8 h post-dose. Pharmacodynamic data suggest that antioxidant effects may represent an important mechanism of action mainly via increased NADH, but additional contributors may include increased glutathione, decreased cell adhesion, and up-regulated autophagy of peripheral blood mononuclear cells. Five papers compared L-Gln with other SCD-modifying therapies. Indirect comparisons suggest that L-Gln, hydroxyurea, and crizanlizumab can each reduce vaso-occlusive events with significant decrease of pain crises and hospitalizations. However, direct comparative efficacy cannot be established in the absence of head-to-head trials. Overall safety profile was also comparable; however L-Gln may cause more gastrointestinal (GI) side effects such as constipation and abdominal pain. Annual cost of L-Gln is lower than crizanlizumab, however insurance denials and high co-pays were reported as barriers to initiating the therapy. Conclusion: Oral L-Gln is an effective SCD-modifying therapy for patients with sickle cell disease 5 years and older. Gastrointestinal adverse effects, including abdominal pain and constipation, are reported. PK supports twice daily regimen, and PD suggests that anti-oxidative effect is the dominant MOA. Cost reductions may result in wider use of L-Gln.