Safety, tolerability, and pharmacokinetics of 6-diazo-5-oxo-L-norleucine (DON) in Malawian adults with and without malaria: a Phase I dose-escalation clinical trial

Authors

• Brittany A. Riggle, Laboratory of Immunogenetics, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
• Athanasios Chamzas, Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD  USA.
• Mathangi Gopalakrishnan, Center for Translational Medicine, University of Maryland School of Pharmacy, Baltimore, MD  USA.
• Osward M. Nyirenda, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Nginache Nampota-Nkomba, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Jane E. Mallewa, Department of Internal Medicine, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Rhoda Masonga, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Cynthia Manyozo, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Kingsley Zuze, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Alice M. Liomba, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Jesse Alt, Johns Hopkins Drug Discovery and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Rana Rais, Johns Hopkins Drug Discovery and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Barbara Slusher, Johns Hopkins Drug Discovery and the Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
• Neshen Moodley, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
• Louis H. Miller, Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
• Susan K. Pierce, Laboratory of Immunogenetics, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
• Nicole O'Brien, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.
• Matthew B. Laurens, Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
• Douglas G. Postels, Blantyre Malaria Project, Kamuzu University of Health Sciences, Blantyre, Malawi.

Document Type

Journal Article

Publication Date

2-26-2026

Journal

The Journal of infectious diseases

DOI

10.1093/infdis/jiag121

Keywords

6-diazo-5-oxo-norleucine; Cerebral malaria; DON; IND drug study; Phase I; safety; tolerability

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 I clinical trial of single dose intravenous DON in Blantyre, Malawi. Participants included healthy adults and adults with uncomplicated malaria, enrolled in dose-cohorts of ten 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 post-infusion 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 1.7-4.1 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.ClinicalTrials.gov: NCT05478720.

APA Citation

Riggle, Brittany A.; Chamzas, Athanasios; Gopalakrishnan, Mathangi; Nyirenda, Osward M.; Nampota-Nkomba, Nginache; Mallewa, Jane E.; Masonga, Rhoda; Manyozo, Cynthia; Zuze, Kingsley; Liomba, Alice M.; Alt, Jesse; Rais, Rana; Slusher, Barbara; Moodley, Neshen; Miller, Louis H.; Pierce, Susan K.; O'Brien, Nicole; Laurens, Matthew B.; and Postels, Douglas G., "Safety, tolerability, and pharmacokinetics of 6-diazo-5-oxo-L-norleucine (DON) in Malawian adults with and without malaria: a Phase I dose-escalation clinical trial" (2026). GW Authored Works. Paper 8664.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8664

Department

Neurology