Pharmacokinetics and Toxicokinetics of Artemisinin-Hydroxychloroquine Sulfate Tablets in Rats and Dogs

Abstract

Artemisinin-hydroxychloroquine sulfate tablets (AH) are relatively inexpensive and a novel combination therapy for the treatment of all forms of malaria, especially aminoquinine drug-resistant strains of P. falciparum. Our aim was to assess the pharmacokinetics (PK) and toxicokinetics (TK) of AH following oral administration in Sprague Dawley rats and Beagle dogs by using the liquid chromatography tandem mass spectrometry methods (LC-MS/MS). The PK studies were carried out in eighteen rats at three doses and six dogs at three rounds of three doses after a single oral administration of AH. The TK studies in rats and dogs were accompanied by the 14-day repeated dosing studies. The PK results revealed that artemisinin was absorbed and cleared rapidly in rats with obvious gender difference and interindividual variability, and the systemic exposure with regard to AUC was positively correlated with the dosage in female rats. However, the kinetics parameters of artemisinin in dogs were not obtained because the plasma concentration was undetectable. The absorption and elimination of hydroxychloroquine in dogs and rats were relatively slow, and no gender difference was observed. The AUC of hydroxychloroquine showed a linear correlation with the dosage, but Cmax varied significantly among individuals. After 14-day repeated oral administration of AH, hydroxychloroquine shows an increase in systemic exposure and accumulation in rats and dogs, whereas the AUC and Cmax of artemisinin remarkably decreased in female rats due to its autoinduction metabolism. The TK results were basically consistent with the dose- and time-dependent toxic reaction in 14-day repeated dosing studies of AH in rats and dogs. The information from our studies could be helpful for further pharmacological and toxicological research and clinical application of AH.

2‐Deoxyglucose and hydroxychloroquine HPLC‐MS–MS analytical methods and pharmacokinetic interactions after oral co‐administration in male rats

“…The instrument settings and performance metrics are described in detail in Figure A5. The LLOQ for HCQ was 10 times improved over two recently reported LC–MS/MS methods 10,11 …”

“…The observed C max values for HCQ were in good agreement with reported values by other authors. For example, in rats orally dosed with low, mid, and high doses of HCQ and artemisinin combination tablets, corresponding to an intake of 82, 165, and 331 mg HCQ/kg, the plasma C max mean values were 402, 623, and 868 ng HCQ/mL, respectively 11 . A 2023 preprint in Medrxiv (https://www.medrxiv.org/content/10.1101/2023.06.22.23291702v1) documented an oral dosing of 13.3 mg HCQ/kg to rats resulting in C max of 90 ng HCQ/mL plasma and 183 ng HCQ/mL whole blood.…”

Evaluation of gender differences in the pharmacokinetics of oral zileuton nanocrystalline formulation using a rat model

“…Several studies have shown pharmacokinetic evidence of reduced clearance in female rats ( Li et al, 2021 ; Arora et al, 2021 ; Zhou et al, 2002 ; Czerniak, 2001 ). Gender differences in clearance mechanisms are complex and may depend on the formulation ( Soldin et al, 2011 ).…”

Therapeutic potential of artemisinin and its derivatives in managing kidney diseases

“…In addition, the absorption of artemisinin in the body has apparent gender and individual differences. After continuous oral administration of artemisinin in rats for five days, the AUC0∼t of females and males decreased by 63.5% and 56.4%, and the maximum plasma concentration (Cmax) decreased by 66.8% and 55.8% ( Li et al, 2021 ).…”