Naphthoquine-induced Central Nervous System and Hepatic Vasculocentric Toxicity in the Beagle Dog

Abstract

Naphthoquine phosphate (NP) was considered as a partner drug with a promising antimalarial drug candidate. Here we report unexpected adverse clinical signs and microscopic findings in a canine pilot toxicology study with NP. Male and female dogs were dosed daily by oral gavage with NP at 2, 10, or 50 mg/kg/day for a maximum of 14 days. NP was not tolerated at ≥10 mg/kg/day; several animals were sacrificed in moribund condition and marked neurological clinical signs were noted at 50 mg/kg/day. The main microscopic observation was central nervous system vasculocentric inflammation (mainly lymphocytes and macrophages) in the white and gray matter of various regions of the brain at ≥2 mg/kg/day and at lower incidence in the spinal cord at ≥10 mg/kg/day. Vasculocentric microscopic changes predominantly centered on the centrilobular vein were also observed in the liver at ≥2 mg/kg/day. Females were more sensitive than males with comparable NP plasma exposure. In conclusion, under the conditions of this study, the administration of NP to dogs via daily oral gavage for up to 2 weeks was not tolerated causing moribundity, marked neurological clinical signs, and vasculocentric microscopic changes in the central nervous system and the liver.

Population Pharmacokinetics of Antimalarial Naphthoquine in Combination with Artemisinin in Tanzanian Children and Adults: Dose Optimization

“…There is increasing interest in developing novel or updated combination therapies, particularly single-dose therapies, as alternatives to current 3-day regimens in sub-Saharan African countries where malaria is endemic, including Tanzania. Previously, one such combination considered was artemisinin and naphthoquine prior to recent and unexpected toxicity findings in animal toxicity studies ( 15 ). Several studies have examined the pharmacokinetic properties of artemisinin in populations from areas of malaria endemicity when the drug is given alone or in combination with other partner drugs as a single-dose therapy.…”

“…Despite the dose being well tolerated, with no serious adverse events in humans, QTc prolongation has been observed in children on artemisinin-naphthoquine 4 h after the third dose in PNG (when given as a 3-day regimen) ( 50 ). There have also been reports of central nervous system and hepatic vasculocentric toxicity in beagle dogs ( 15 ). Our recommended dose regimen was constructed to ensure that the median day 7 plasma naphthoquine concentration was above 5th percentile of the predicted target.…”

“…Our recommended dose regimen was constructed to ensure that the median day 7 plasma naphthoquine concentration was above 5th percentile of the predicted target. There is a need to evaluate the safety and tolerability of any increased doses, considering the toxicity previously reported ( 15 , 50 ).…”

“…Furthermore, the resulting model will be used to explore alternative optimal dosage regimens via simulation. Since the study reported here, naphthoquine was found to be associated with a potential for toxic side effects ( 15 ); however, its role in antimalaria treatment is unclear. Nevertheless, we report results for future pharmacokinetic and exposure studies.…”

“…However, despite the potential that a single dose may improve adherence, cure rates with any new ACT, including ART-NQ, should be ensured or improved with multiday dosing ( 13 , 14 ), and there is thus a need to assess both the efficacy and pharmacokinetics (PK) of different regimens of ART-NQ or new ACTs. Unfortunately, naphthoquine was recently shown to be potentially associated with induced central nervous system toxicity in animal studies as well as hepatic vasculocentric toxicity ( 15 ). Here, we report for completeness previous pharmacometrics and model-based assessment of naphthoquine completed prior to new toxicity studies.…”