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 C _max 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 C _max 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.

Figure 1

Representative chromatograms for hydroxychloroquine, artemisinin, and the internal standards in rat plasma: (a) blank plasma sample, (b) blank plasma sample spiked with the IS, (c) LLOQ sample spiked with the IS, and (d) rat plasma sample 1 h after the oral dose of AH.

Figure 2

Mean plasma concentration-time curves of hydroxychloroquine (a) and artemisinin (female (b) and male (c)) in rats after a single oral administration at low, medium, and high doses of AH (191, 382, and 764 mg/kg).

Figure 3

Mean plasma concentration-time curve of hydroxychloroquine in Beagle dogs after a single oral administration at low, medium, and high doses of AH (53.8, 107.6, and 215.2 mg/kg).

Figure 4

Mean plasma concentration-time curve of hydroxychloroquine (a) and artemisinin (female (b) and male (c)) in rats after oral administration of AH at doses of 146, 219, 328, and 492 mg/kg on day 1 and day 14 during the course of the repeated dose TK study.

Figure 5

Mean plasma concentration-time curve of hydroxychloroquine in dogs after oral administration at low, medium, and high doses of AH (56, 84, and 126 mg/kg) on day 1 and day 14 during the course of the repeated dose TK study.