Pharmacokinetics of the Antimalarial Drug, AQ-13, in Rats and Cynomolgus Macaques

Abstract

The purpose of this study was to evaluate the bioavailability and pharmacokinetics of a new antimalarial drug, AQ-13, a structural analog of chloroquine (CQ) that is active against CQ-resistant Plasmodium species, in rats and cynomolgus macaques. Sprague-Dawley rats (n = 4/sex) were administered a single dose of AQ-13 intravenously (i.v.) (10 mg/kg) or orally (20 or 102 mg/kg). Blood and plasma samples were collected at several timepoints. AQ-13 achieved C(max) after oral administration at approximately 3 to 4 h and could be detected in blood for 2 to 5 days after oral administration. The ratio of area under the curve (AUC) values at the high and low dose for AQ-13 deviated from an expected ratio of 5.0, indicating nonlinear kinetics. A metabolite peak was noted in the chromatograms that was identified as monodesethyl AQ-13. Oral bioavailability of AQ-13 was good, approximately 70%. The pharmacokinetics of AQ-13 was also determined in cynomolgus macaques after single (i.v., 10 mg/kg; oral, 20 or 100 mg/kg) and multiple doses (oral loading dose of 50, 100, or 200 mg/kg on first day followed by oral maintenance dose of 25, 50, or 100 mg/kg, respectively, for 6 days). The AUC and C(max) values following single oral dose administration were not dose proportional; the C(max) value for AQ-13 was 15-fold higher following an oral dose of 100 mg/kg compared to 20 mg/kg. Monodesethyl AQ-13 was a significant metabolite formed by cynomolgus macaques and the corresponding C(max) values for this metabolite increased only 3.8-fold over the dose range, suggesting that the formation of monodesethyl AQ-13 is saturable in this species. The bioavailability of AQ-13 in cynomolgus macaques following oral administration was 23.8% for the 20-mg/kg group and 47.6% for the 100-mg/kg group. Following repeat dose administration, high concentrations of monodesethyl AQ-13 were observed in the blood by day 4, exceeding the AQ-13 blood concentrations through day 22. Saturation of metabolic pathways and reduced metabolite elimination after higher doses are suggested to play a key role in AQ-13 pharmacokinetics in macaques. In summary, the pharmacokinetic profile and metabolism of AQ-13 are very similar to that reported in the literature for chloroquine, suggesting that this new agent is a promising candidate for further development for the treatment of chloroquine-resistant malaria.

Randomized Dose-Ranging Controlled Trial of AQ-13, a Candidate Antimalarial, and Chloroquine in Healthy Volunteers

“…Second, they demonstrate that AQ-13, an AQ analogous to CQ, has similar linear pharmacokinetics in human volunteers, despite the fact that it requires a larger dose to achieve equivalent drug exposure because of a more rapid clearance. These results are also consistent with the preclinical studies, which suggested that the AEs of AQ-13 and CQ would be similar and that a dose adjustment would be necessary for AQ-13 because of its more rapid clearance [17,18]. Because this Phase I study has demonstrated the safety of AQ-13 doses up to 1,750 mg, the next logical study (after examining the effects of a fatty meal on the absorption of AQ-13) is a dose-finding efficacy (Phase 2) study in humans with uncomplicated P.…”

“…Because AQ-13 was cleared more rapidly than CQ in the preclinical studies [17,18], the protocol for the Phase I human studies included a dose adjustment step after the 600 mg dose (Figure 1). Because the information available about the effects of CQ on the QT interval was limited [28,29], these studies used Holter recordings to compare the effects of CQ and AQ-13 on the QT interval.…”

“…After AQ-13 had been selected as the initial lead compound, preclinical studies were performed to examine its toxicology and pharmacokinetics in animals in comparison with CQ [16,17]. Because those studies revealed no differences in toxicity between AQ-13 and CQ and similar pharmacokinetics, an Investigational New Drug Application was filed with the US Food and Drug Administration (IND 55,670) [18].…”

Alternatives to currently used antimalarial drugs: in search of a magic bullet

“…Preclinical studies have indicated increased efficacy of AQ-13 when compared to other derivatives [50]. Phase I first-in-human safety and efficacy studies have shown results similar to those observed with chloroquine.…”

Malaria-Infected Mice Are Cured by a Single Low Dose of a New Silylamide Trioxane Plus Mefloquine

“…Progress in chemotherapy has been made using protease inhibitors to starve the parasites [5,6], using antimalarial acridones [7] and new 4-aminoquinolines [8] to counteract resistance, and using some modified chloroquine analogs [9]. Trioxanes derived from artemisinin (1), such as artemether ( 2c ) and sodium artesunate ( 2d ), are now being used clinically to cure malaria-infected people [10,11,12,13,14,15,16].…”