064: Pharmacokinetics of 6-diazo-5-oxo-L-norleucine (DON) in Malawian Healthy Adults & Adults With Uncomplicated Malaria

Statement of Purpose, Innovation or Hypothesis: Cerebral malaria (CM) is the deadliest manifestation of Plasmodium falciparum infection. In endemic areas, CM almost exclusively affects young children. CM survivors commonly have lifelong neurological impairments. Current CM treatment includes intravenous artesunate-based antimalarials and supportive care. Previous clinical trials of adjunctive CM therapies have failed to decrease rates of mortality or neurological morbidity. In pre-clinical studies, 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, has demonstrated potential efficacy in mouse models. DON was safe and well tolerated in previously completed cancer clinical trials. As part of a Phase I/IIa clinical trial of adjunctive DON in children with CM, we first evaluated the tolerability and pharmacokinetics (PK) of DON in an adult population. The Malawian adult population we studied was stratified by malaria status. In the adult portion of the study, we endeavored to (i) characterize the PK of DON in healthy adults and adults with uncomplicated malaria, (ii) evaluate the effect of malarial infection on the PK characteristics of DON, and (iii) inform dosing in children with CM.

Description of Methods & Materials: We performed a single-dose, dose-escalation, open-label Phase I clinical trial in Malawian adults divided into two participant groups: healthy adults and adults with uncomplicated malaria receiving antimalaria lumefantrine-artemether treatment. Participants received one of four possible concentrations of intravenous DON with doses ranging from 0.1 mg/kg to 10 mg/kg. Plasma concentrations of DON at 8 timepoints post-administration were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by standard non-compartmental (NCA) PK analysis, using Pumas (JuliaPro Version 1.7.2, Pumas Version 2.4.0).

Data & Results: In total, 78 adult participants were enrolled: 40 healthy adults and 38 adults with uncomplicated malaria. The mean semi-logarithmic plasma concentration profiles of DON showed a bi-exponential decay in both populations, suggesting multi-compartmental PK (Figure 1). There was a dose proportional increase in exposure for DON in healthy adults and a greater than dose proportional increase in adults with uncomplicated malaria in the studied dose ranges. For adults with uncomplicated malaria, DON exposure (AUC_inf) was generally lower in 0.1–1.0 mg/kg dose groups (27–36% decrease) compared to healthy adults but comparable or higher at doses 5.0–10.0 mg/kg (13–38% increase), showing a trend of decreasing clearance with the increasing dose (Table 1). T_1/2 ranged between 2.7–4.2 hours for healthy adults and 1.7–4.0 hours for adults with uncomplicated malaria. PK parameters of DON in Malawian healthy adults and those with uncomplicated malaria (AUC_inf; 31040 and 42950 μg⸱h/L for 10.0 mg/kg, respectively) were similar to prior studies in cancer patients in the United States (AUC_inf 50470 μg⸱h/L for 11.5 mg/kg).

Interpretation, Conclusion or Significance: The PK of DON was characterized in healthy adults and adults with uncomplicated malaria. The magnitude of differences in the overall exposure of DON between adults with and without uncomplicated malaria was within 30–40%, potentially indicating minimal effect of malarial infection on DON’s PK properties. The rich PK sampling data from adults will facilitate the population PK analysis in children with CM, where sampling is designed to be sparse.

Disclosures: The authors have nothing to disclose.

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