Safety, Tolerability, and Pharmacokinetics of 6-Diazo-5-Oxo-L-Norleucine in Malawian Adults With and Without Malaria: A Phase 1 Dose-Escalation Clinical Trial

Clinical Snapshot

Key Findings

• P Value: Not provided in abstract

• Effect Size: 18% experienced transient asymptomatic creatinine elevation at 12 hours; dose-dependent nausea and vomiting at 5.0 and 10 mg/kg

• Primary Outcome: Safety and tolerability of single-dose intravenous DON

• Nnt Or Sensitivity: Approximately 5.6 patients treated for one to experience transient creatinine elevation

• Confidence Interval: Not provided in abstract

Clinical Application

Requires intravenous administration and monitoring for renal function and gastrointestinal adverse events Limited direct applicability to Australian practice given rarity of cerebral malaria; may be relevant for tropical medicine specialists managing imported cases or research collaborations African adults and potentially children with cerebral malaria requiring adjuvant therapy

Abstract

BACKGROUND: Cerebral malaria (CM) is a common cause of febrile coma among African children. Despite treatment with highly efficacious intravenous artesunate, CM remains associated with high mortality and neurologic sequelae. In a mouse CM model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) demonstrated robust efficacy as a potential adjuvant therapy. Before testing DON in children with CM, we investigated tolerability in African adults, including individuals with malaria. METHODS: We conducted an open-label, prospective, dose-escalation, phase 1 clinical trial of single-dose intravenous DON in Blantyre, Malawi. Participants included healthy adults and adults with uncomplicated malaria, enrolled in dose-cohorts of 10 and administered DON at 0.1, 1.0, 5.0, or 10 mg/kg. We assessed adverse events (AEs) and plasma pharmacokinetics. RESULTS: Forty healthy adults and 38 adults with uncomplicated malaria received DON. Transient, asymptomatic creatinine elevation occurred 12 hours postinfusion in 18% of all participants. Nausea and vomiting were uncommon at 0.1 and 1.0 mg/kg but occurred more frequently at 5.0 and 10 mg/kg DON. All DON-related AEs resolved rapidly, without sequelae, and did not significantly differ between healthy and uncomplicated malaria participants. In healthy adults, maximum plasma concentrations increased proportional to dose, but adults with malaria had greater than dose-proportional increases. Terminal half-life ranged from 1.7 to 4.1 hours. CONCLUSIONS: DON was well tolerated in healthy adults and adults with uncomplicated malaria. Higher doses were associated with transient gastrointestinal AEs. Pharmacokinetics were minimally influenced by malaria disease. These results provide critical data to guide dosing strategies for adjunctive DON in children with CM. Clinical Trials Registration. NCT05478720.

References

1. 1.Riggle, B. A., Chamzas, A., Gopalakrishnan, M., Nyirenda, O. M., Nampota-Nkomba, N., Mallewa, J. E., Masonga, R., Manyozo, C., Zuze, K., Liomba, A. M., Alt, J., Rais, R., Slusher, B., Moodley, N., Miller, L. H., Pierce, S. K., O'Brien, N. F., Laurens, M. B., & Postels, D. G. (2026). Safety, tolerability, and pharmacokinetics of 6-diazo-5-oxo-L-norleucine in Malawian adults with and without malaria: A phase 1 dose-escalation clinical trial. *The Journal of Infectious Diseases*. https://doi.org/10.1093/infdis/jiag121